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Well the source , bullet proof, is a, um, how do you say questionable at best. This company is trying to sell a brand of coffee lower in toxins and such. Far as I can tell the purpose of this company is to get us to drink more caffeine and sleep less. Sounds wonderful.Here's a post about them from coffee geek :The following lengthy post contains solely my opinions regarding the Bulletproof Coffee advertisement on the internet. My aim is to use the advertisement as a point of departure with which to introduce research that has been performed with many goals that all relate to the presence of naturally occurring toxins in coffee and their supposed effect upon human health. References have been cited to support my opinions, not to disparage or demean in any way the authors or owners of the bulletproof site. My opinions deal solely with the advertisement. I have not brewed or analyzed Upgraded Coffee and I offer no advice or opinion concerning the quality of this product. I neither encourage nor discourage readers from buying it.There has been a mild amount of interest in “Upgraded Coffee” on Coffeegeek and a wider field of interest online since ‘The Bulletproof Executive’ started selling coffee with strong health claims. For those of you who are not familiar or only passingly familiar with this product and these hearth claims, this post is created to express my reaction to the claims of the product with respect to the scholarly publications of food health researchers.Unbiased Reporting, four pitfalls: There is no such thing as unbiased reporting.This author admits to being biased against profiting upon loosely interpreted health-benefits, biased against the misuse of research data and biased against poorly conducted research protocols.In my opinion, Dave Asprey promotes himself as a health guru who seems to me to be the main investor in ‘Better Baby, LLC.’, which seems to own the copyrights to ‘Upgraded Coffee’, ‘Upgradeself.com’ and ‘Bulletproof Coffee’. To be clear, ‘Upgraded Coffee’ is a product you can buy while ‘Bulletproof Coffee’ is a daily regimen, a recipe that you can choose to make. Mr. Asprey seems to be involved in several other self-improvement ventures not related to coffee.Also in my opinion, while refereed professional journals are the best tool for the dissemination of scientific progress currently available, they are also fraught with bias. The scientific authors have a point or thesis that they wish to prove and have it accepted by the larger scientific community. The editors wish to publish cutting-edge research that is most relevant; they do not want their journal to be irrelevant. The board of peer reviewers, the ‘referees’, often have biases based upon their own work or institutional affiliations. This author has submitted articles to refereed journals and has reviewed articles submitted by others for such journals.Finally, each reader of this post holds a bias regarding trust. Do you accept that there will always be bacteria and fungi hitchhiking in the food supply or do you think that zero tolerance for any or all adulterants is the only rational choice? Keep in mind the the European Union, for instance, has set limits for the presence of ochratoxin in roasted and instant coffee but not in green-coffee. In the US, the FDA has not imposed any such limits as of 2013(a).Background on mycotoxinsFungi and bacteria are opportunistic decomposer species that have been waging war with one another for millions of years. Since they both primarily live on dead organic material (exceptions exist), many members of each phylum have evolved a way to poison the other, thereby limiting the influence of the other. Thus, we use bacterial products to retard the growth of mold while antibiotics elaborated by fungi have radically changed our civilization, as in penicillin. It is no secret that a few of the many biological secretions from both groups are toxic to us. This discussion will be limited to the toxins that are most germane to coffee drinkers, aflatoxin B1 and ochratoxin A.This poster is aware that most Coffegeek readers know that we live in a biological sea whereby our mouths, our guts and our skin are colonized by hundreds of species of fungus and bacteria. For the few who do not know this, ‘colonize’ means occupy peacefully, not invade. What is also true is that our food is also covered with bacterial and fungal organisms, sometimes on purpose. Aspergillus is the mold most prevalent on our grains, seeds, nuts, beans, coffee, grapes and many other agricultural products. There are hundreds of species of Aspergillus. Most produce no detectable toxins. From the research, there are perhaps slightly more than a dozen species of Aspergillium and Penicillium that are commonly involved in the production of significant mycotoxins. Are there such things as insignificant mycotoxins? Yes, in my opinion, having read much of the literature. No, if you propose a zero-risk food supply.Aflatoxin B1 is not an insignificant mycotoxin.Health science students have been taught for decades that aflatoxin is the most potent carcinogen (cancer-producing agent) in existence. Within the differences of how this potency is determined among different carcinogens, it still seems to be. Determinations regarding the occurrence, properties or potency of aflatoxin have appeared in over 10,000 scientific publications; it is the most intensively studied toxin. Regarding ochratoxin A, most scholarly papers will close with the admission that more research needs to be done. Far fewer studies have been published for ochrtoxin but many researchers are catching up at present. Ochratoxin A has been implicated in kidney toxicity, immune suppression, cancer and birth defects in animals(b). Studies in Europe have detected small amounts of ochratoxin A in the blood of all of their human subject volunteers (c). The importance for us is that ochratoxin A is the compound found more frequently on coffee beans, although aflatoxin B1 is also found. Aside from their cancer causing properties in animals, both toxins have been implicated in the appearance of other acute and chronic conditions affecting many different organ systems. Specific lung, nervous and kidney diseases have been attributed to mycotoxins. However, mycotoxin injury may be difficult to prove in multiple-cause syndromes such as depression and immune system dysfunction.It is possible that every coffee bean has a few fungal colonies on it. The variables are: is the fungal population too small to detect? If detected, it is there in significant numbers? If fungi are present, are mycotoxins present? If mycotoxins are present, are they below threshold limits for public safety? Finally, do you believe that there are reasonable amounts of mycotoxins that may be ingested without harm?The most important question in the preceding paragraph to some readers may be the last one, but to me it is the middle one: the distinction between the presence of fungi and the presence of toxin. One must not be confused with the other - but in the popular press (blogs), they are. Let us see how the background principles appear in the advertisement for Upgraded Coffee.The ClaimsThe information here ascribed to the sellers of Upgraded Coffee and Bulletproof Coffee is copied from the pertinent sections of the routinely publicly-accessible web pagewww.bulletproofexec.com/coffee/. Most footnotes belonging to bulletproofexec.com (numbers) are not reproduced in this post, a few are, but they may be accessed from their website, with the exception of the expired links. My footnotes are given by (letters).First, Bulletproof Coffee is a recipe made by adding high-quality butter and medium chain triglyceride oil to brewed Upgraded Coffee. Your own opinions and experience regarding dietary supplements and coffee and the roles that they play in your life will determine your interest or disinterest in this recipe.Next, Upgraded Coffee is a roast sold with the following claims. Please be aware that this advertiser uses the practice of making a supported claim, then following it immediately with an unsupported opinion that is not reflected in the supporting literature that was cited.They claim:• 52-91.7% of green coffee beans are contaminated with mycotoxins.(1) 50% of brewed coffee beans are moldy.(2)The first paper cited actually states that 91.7% of all samples were contaminated with molds, not with mycotoxins. Thirty three percent of the 60 samples collected demonstrated the measurable presence of mycotoxins. The paper gave no details on from how widely the 60 samples were collected(d). One Brazilian plantation? Sixty Brazialian plantations? One bag? Sixty bags?The second paper cited actually determined that 50% of 25 samples measured positive for ochratoxin A, not mold. Furthermore, the paper's authors state: “Five samples … originated from spoiled coffee lots which were expected to contain high amounts of OA [ochratoxin A] and would not have been marketed”(e).• Caffeine protects coffee beans from mold. Decaf coffee is higher in ochratoxin (3) and aflatoxin. (4)Multiple studies have confirmed this as accurate.• Mycotoxins cause cardiomyopathy (5), cancer (6), brain damage (7) and hypertension and kidney disease. (8) They also make your coffee taste bitter. You want to avoid mycotoxins as much as possible.Multiple animal studies have implicated mycotoxins in all of the diseases mentioned. Researchers then infer that mycotoxins can cause similar diseases in humans, but this remains difficult to prove. Concerning the taste, how would they know? It would be unethical to subject tasting panels such as the National Food Laboratory or even random volunteers to known contaminated coffee. In my opinion, this statement capitalizes upon the dissatisfaction many coffee drinkers have expressed regarding the quality of their home brew. Given the many factors responsible for bitterness in coffee, it would seem indefensible to relate the taste back to a moldy sack of green coffee beans. The last sentence [You want to avoid mycotoxins as much as possible.] is opinion, but who would disagree?• 10-60% of ochratoxin is not destroyed by roasting. (9)This reference link appears to have expired . The heat destruction, specifically for coffee roasting, of both aflatoxin and ochratoxin has been the subject of quite a few scientific papers. Given the great variability in roasting techniques, it is no surprise that reports of the destruction of mycotoxins with roasting varies greatly from a 10% decrease to a complete destruction of all mycotoxins reported among many publications, only three of which I will cite here(f,g,h). Perhaps highly significant to the discussion regarding the destruction of mycotoxins by roasting is the global perspective offered by the abstract of the following reference:”This report reviews studies concerning the susceptibility of green coffee beans to mycotoxin contamination. Included are investigations on normal mold flora, toxin production in inoculated beans, effect of experimental roasting on aflatoxin, ochratoxin, and sterigmatocystin, and survey on the presence of these toxins in commercial green coffee. Because of the extremely low frequency of findings, the low levels of toxins, and the experimental data showing 70--80% destruction by the roasting process of toxin added to green coffee, further study on this topic has been discontinued”(i).• Another study found 4-31% of ochratoxin remains after roasting. (10) This is why it’s crucial to avoid mycotoxins during every step of the production process, not just after the beans are roasted.See above. Cited statement followed by statement of opinion.• Coffee that is not processed soon after harvest gets more mold than quickly processed coffee. (11)This is true(j).• Coffee develops more mold when it is left to sit, which is how most large scale coffee manufacturers produce their coffee. (12)“Hence, speedy processing is highly desirable in order to obtain maximum quality”, according to Sivetz and Desrosier (k). Some fermentation, at least 6 hrs. worth, seems necessary in order to dissolve the coffee mucilage layer; see below.• Coffee is the number one source of antioxidants for Americans. (13) Unfortunately, it is also one of the largest sources of mycotoxins. Bulletproof® Upgraded™ Coffee allows you to reap the benefits of coffee while avoiding the side effects.Citation refers to an informal statement made by a researcher at the 2005 meeting of the American Chemical Society. The author has over 40 publications on antioxidants and therefore does seem to be a credible source. Supported statement is followed by unsupported opinion.• Roasted coffee beans have a higher antioxidant content (14) which is why we use a special roasting process for Bulletproof® Upgraded™ Coffee Beans.Higher than what? Green coffee? In fact, this interpretation is exactly the opposite of what was proven by the cited research. To quote the abstract from their reference #14: “Data from this study suggested that natural phenolics present in NRC [non-roasted coffee beans] had higher antioxidant activity compared to MRPs (Maillard reaction products) derived from coffee and model MR (Maillard reaction ) systems. However, MRPs were the prevailing antioxidants in RC (roasted coffee) as free CGA (one of the natural phenolics) waslost (>90%)”(Italics mine)(l).• Moderate doses of caffeine improve mental performance. (15)• Caffeine influences gene expression in a way that protects your brain. (16)• The caffeine coffee is a powerful antioxidant that can even protect against Alzheimer’s. (17)• Caffeine is an ergogenic aid, meaning it increases power output. This is true for both aerobic (18) and anaerobic exercise. (19)• Coffee consumption is associated with higher adiponectin levels in Japanese males.(20) High adiponectin levels are associated with increased metabolic health.These are all promotions for the benefits of caffeine, which is beyond the intent of this post and not unique to Upgraded Coffee. Parenthetically, I have a very dim opinion of anyone making a claim that caffeine protects humans from Alzheimer’s disease. Their reference #17 is a popular press website that quotes an article in the Journal of Physical Chemistry. Along the way, the phrase ‘may help protect’, quoted second-hand, has been turned into ‘can even protect’ in the above extract from the bulletproofexec.com website.To continue, Upgraded Coffee enumerates the following steps in its coffee production:It is carefully produced and tested with new and old methods to target the lowest toxin content vs. normal coffee, so you get all the benefits of coffee without the negative health effects.The beans are harvested from a single family-owned estate in Guatemala located 1250 meters above sea level, high enough to produce great coffee.The estate is Passive Organic and the family that owns it does not allow chemicals (herbicides, pesticides, etc.) It is not economical for Central American boutique coffee estates to become certified organic.They are hand picked by experienced coffee harvesters – skilled people who know how to pick only perfectly ripe berries.Most coffee beans are processed by either leaving them in the sun and elements to wither and dry, or by pressing them and letting them ferment (spoil) to remove the outer layer of the bean. Both of these techniques are known to produce significant levels of mycotoxins as they enhance flavor. Upgraded™ Coffee beans are mechanically processed right after picking using only clean cold water. This more expensive process is safer because it dramatically reduces harmful molds or bacteria from impacting your health.The beans are roasted in small batches by the #1 ranked roaster in United States under the strictest conditions. Roasting the beans enhances their antioxidant capacity and flavor to provide you with a healthier, tastier cup of coffee.Upgraded Coffee is manufactured using parameters that are trademarked and therefore proprietary. This means that they do not have to describe how their manufacturing is different, just that it is different enough to allow them to trademark it. Whether the difference is significant or not to quality does not matter to the process of trademark application unless such application is challenged.Steps 1 through 5 do not impress me as being different from the procedures than any buyer, purveyor or roaster of quality single origin or varietal blend washed coffee now uses. Readers who are professionally involved in the coffee trade are welcome to correct or confirm my assumption in this regard.Regarding step #5, quality plantations process the coffee cherries quickly, according to Sivetz and Desrosier in the source cited. Coffee production is divided into natural and washed coffee. More than half of the world’s coffee is natural coffee, hence the first sentence in step #5 is correct (m,n). Coffee cherries consist of the central seed or bean with a thick, slimy mucilage coating, all enclosed by a layer of pulpy flesh, surrounded by skin. Washed coffee uses a combination of mechanical scrubbing and washing with water because water alone cannot disperse the stubborn mucilage coating. “The mucilage is insoluble in water. … It clings to the coffee too tenaciously to be dispersed and removed by simple washing” (o). Nor can unlimited force be brought to bear on the mucilage because quality coffee demands that the underlying parchment or ‘silver skin’ enclosing the coffee bean be left intact until intentional hulling is carried out (p). Removing the mucilage appears to be the largest obstacle standing between harvesting and drying the coffee beans. Because of the complexity of cleaning coffee beans, proprietary methods abound. Most plantations use fermentation to soften and remove the mucilage and fermentation may last from as little as six hours to three days. Gentle mechanical scrubbing is useful in shortening fermentation time (q). For all competent plantations, sanitation and avoiding fungal and bacterial spoilage results in good tasting, commercially successful coffee (r).Molding may occur during storage. For all their talk about ‘cradle to grave’ protection from mycotoxins, the authors of the bulletproofexec.com website make no specific mention on how their crop is stored. It is my opinion that a multiple-project self-help enterprise that contracts out its coffee roasting (see next P) is likely to own no coffee storage facilities, and to exert little or no oversight upon shipping or storage.Step#6 tells us that Upgraded Coffee is not a roaster and therefore exerts little control over the roast batches. True, the roaster agent should meet the specifications elaborated by their client but how much oversight does Better Baby, LLC, Upgraded Coffee or David Asprey exert upon the roaster? I am assuming that coffee is a side line of a self-help professional. Is there someone who is a professional coffee buyer who works with the roaster? I emailed the organization because I was curious who the roaster was. Several weeks later......I received a reply. They are roasted by Portland Roasting, a business that seems to be independent of Better Baby, LLC.. Portland Roasting's web site appears to be that of a sincere, ecologically-minded and globally-ethical company. They play up their charitable projects in some 16 countries associated with their coffee-buying but say nothing about paying attention to mycotoxins. The mycotoxin preoccupation seems solely in the lap of bulletproofexec. Portland Roasting was awarded Roaster of the Year in 2012 by Roast Magazine. I suppose this makes them the #1 roaster. At least for a year.According to the website, Upgraded Coffee will stay fresh for up to a year in the sealed package and up to 3 to 4 weeks after it’s been opened. However, hey state that Upgraded Coffee is best enjoyed within two weeks of receipt. The last sentence sounds plausible, but when was it roasted? This style of coffee preservation belongs in the domain of 'supermarket roasts' which have been given poor marks by multiple posters on the Coffeegeek forums.Finally, let us not forget the forest of disclaimers that stalk the bottom of every website. In the case of Upgraded Coffee, despite their claims, these include:California Prop 65 Warning: Chemicals known to the State of California to cause cancer and reproductive toxicity may be present in dietary supplements, nutritional food powders, grocery items and other products sold at UpgradedSelf.com.Some or all of the products you may order from UpgradedSelf.com may contain these chemicals. These chemicals are not added to the products but are naturally occurring in many of the starting raw materials (ingredients) and/or result from the processing (cooking) of some of the food products. When you buy products from UpgradedSelf.com, you verify that you have read the CA Prop 65 warning and purchase the products with full knowledge.This supports my opinion that we live among a universe of microbes and it is impossible to drink coffee that is free from ochratoxin A and other unwanted compounds.Finally, to balance anyone’s concern that they must give up coffee for the sake of health, here let me state that mycotoxins are everywhere and coffee may guard you against mycotoxin injury. Regarding the first point, as one reads the mycotoxin literature, other foods carrying mycotoxins are mentioned as being more prevalent and having higher levels. Studies of retail foods in Japan reported 10 of 21 samples of peanut butter contained aflatoxin, and ochratoxin A was found in 7 of 10 samples of rye, 24 of 50 samples of wheat flour, 12 of 20 samples of beer, 6 of 10 samples of wine, 7 of 11 samples of raisins, 3 of 9 samples of roasted coffee and 2 of 11 samples of green coffee. The concentration of ochratoxin was way below EU thresholds for public safety in all samples. Roast coffee averaged half the levels found in green coffee but green coffee had one third the levels found in raisins (s). In an extension of this research, aflatoxins were also found in 22 of 44 samples of ‘bitter chocolate’ (sorry, you chocolate lovers) (t). In the European paper cited previously, the source of the ochratoxin found in the blood of study volunteers was stated to be primarily from cereals (u).With respect to the protective effects of coffee, biochemical studies suggest that several components of brewed coffee activate cellular defense mechanisms with the result that toxins are detoxified or their mutagenic effects are blocked. These beneficial substances are caffeine and quite a few other substances such as several polyphenols and diterpenes, two, in particular: kahweol and cafestrol(v,w).In summary, all coffee drinkers are exposed to aflatoxins, ochratoxin A and other fungal toxins and exposure cannot be avoided. However, their contribution to human disease is completely unknown since all known disease effects take place in animal studies or in cell cultures. In my opinion, the diet of the developed world offers too many competing toxins and dietary indiscretions that kill and maim us before the toll of mycotoxins could ever be significant. For instance, the worst effect of aflatoxin is liver cancer, but liver cancer in the developed world is always preceded by cirrhosis (in which aflatoxin isnot implicated) with very, very few exceptions (I am not going to cite this – it is easy to find out if you take issue with this opinion). Also, mycotoxins are carried by hundreds of food products, not just coffee. Chocolate, raisins, peanuts and wheat seem especially prone to contamination. Also in my opinion, coffee harvesting, processing and storing that optimizes the quality and sale value of a coffee harvest also serves to minimize the conditions under which fungi grow. As long as dedicated buyers for George Howell’s Terroir, Intelligentsia and dozens of other roasters are prowling the world’s coffee plantations for the source of that ‘God shot’, there seems to be little reason to worry about the level of mycotoxins to which aficionados are exposed. That does not mean the coffee trade should not be monitored for safety and it does not mean that all coffees have the same level of purity; studies have incidentally reported higher levels of ochratoxin A in instant coffee than in beans and the EU limits for ochratoxin A in instant coffee is twice the limit for roast beans. Finally, just as coffee is a complex chemical solution, its biochemical effects are just as complex. The answer to why coffee beans use their energy to produce so many compounds, caffeine chief among them, may lie in the conjecture that they, too, are fighting chemical warfare, in this case against bacteria, fungi and mycotoxins and that, by ingesting this marvelous broth, we, too, are enjoying the protective effects of their defenses.Bayman P, Baker JL. Ochratoxins: A global perspective. Mycopathologia (2006) 162: 215-223.Ibid.Ibid.Martins ML, Martins HM, Gimeno A. Incidence of microflora and ochratoxin A in green coffee beans (Coffee Arabica). Food Addit. Contam. (2003) 20(12):1127-31.Studer-Rohr I, Dietrich DR, Schlatter J, Schlatter C. The occurrence of ochrtoxin A in coffee. Food Chem Toxicol. 1995. 33(5):341-55.Soliman KM. Incidence, level, and behavior of aflatoxins during coffee bean roasting and decaffeination. J Agric Food Chem. 2002 Dec 4;50(25):7477-81.Micco C, Miraglia M, Brera C, Desiderio C, Masci V. The effect of roasting on the fate of aflatoxin B1 in artificially contaminated green coffee beans. Mycotoxin Res. 1992 Sep;8(2):93-7.Powrie WD, Wu CH, Molund VP. Browning reaction systems as sources of mutagens and antimutagens. Environ Health Perspect. 1986 Aug;67:47-54.Levi C. Mycotoxins in coffee. J Assoc Off Anal Chem. 1980 Nov;63(6):1282-5.Sivetz M and Desrosier NW, “Harvesting and Handling Green Coffee Beans” in Coffee Technology pp. 74-116, 1979. AVI Publications.Sivetz, op. cit. p 81.Yazheng L, Kitts DD. Confirmation that the Maillard reaction is the principle contributor to the antioxidant capacity of coffee brews. Food Res Intl (2011) 44(8):2418-24.Sivetz M and Desrosier NW. Op. Cit. pg 81.http://www.ico.org/field_processing.aspSivetz, op. cit. p 97.Ibid.Sivetz, op. cit. p 103.Sivetz, op. cit. pp. 78,79,81,82,83,87,88,97,102.Sugita-Konishi Y, Nakajima M, et. Al. Occurrence of aflatoxins, ochratoxin A, and fumonisins in retail foods in Japan. J. Food Prot. (2006) 69(6):1365-70.Kumagai S, Nakajima M, et. Al. Aflatoxin and ochratoxin A contamination of retail foods and intake of these mycotoxins in Japan. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2008 Sep;25(9):1101-6.Bayman P, Baker JL. Op. Cit.Cavin C, Marin-Kuan M, et. Al. Induction of Nrf2-mediated cellular defenses and alteration of phase I activities as mechanisms of chemoprotective effects of coffee in the liver. Food Chem Toxicol. 2008 Apr;46(4):1239-48.Huber WW, Parzefall W. Modification of N‐Acetyltransferases and Glutathione S‐Transferases by Coffee Components: Possible Relevance for Cancer Risk. Methods Enzymol. (2005) 401:307-41.back to topscjavadrSenior MemberJoined: 14 Feb 2010Posts: 49Location: SCExpertise: I love coffeePosted Thu May 30, 2013, 7:38pmSubject: Re: Upgraded Coffee, Bulletproof Coffee, Mycotoxins and HealthWow! Thanks for taking the time to do this. I've been discussing this with some of my CrossFit friends who were intrigued by the claims of Bulletproof Coffee and have played around with their Upgraded Coffee, and who have since stopped drinking that. I discussed my informal opinions regarding what I know from my biology days, which seems to be along the same track described in your post, but you have definitely done a lot of work to put that together. Glad to read a non-promoting analysis of the product.back to topBuckleySenior MemberJoined: 25 Jan 2011Posts: 424Location: InternetExpertise: I love coffeePosted Fri May 31, 2013, 3:25amSubject: Re: Upgraded Coffee, Bulletproof Coffee, Mycotoxins and Health

The self reported figures of AA are widely believed - both inside and outside the fellowship - to have been greatly exagerrated. For example, the “first 100” referred to in the Big Book were in fact around 40 people, of these, about 8 had been sober for over 6 months at the time the book was written. They did not use the 12 Steps: these were invented for the purpose of the book by Bill W, who adapted them from the precepts of the Oxford group.The first 100 had not been attending AA, technically speaking. They had been engaging in modified versions of the Oxford group’s home church meetings. In this setting what is now called “sharing” was originally called “confession” - it was changed because it clashed with the RC church’s prohibition on public confession. They used a methodology originally proposed by the Oxford group of making confession in the form of funny stories and laughing at themselves.The central belief of the Oxford movement was in the doctrine of Total Depravity. This is a Christian doctrine that proposes that since the Fall, mankind has been powerless not to sin without petitioning for direct divine intervention. This too is very evident throughout the Steps.The sample size - 40 people (or even a hundred) - is not big enough to be generalisable and meaningful. Later claims were similarly unsupported: the assertion that half got it right away, for example, is often quoted but not evidenced anywhere.Bill Wilson’s original intent, which is very clear through the unchanged portions of AA literature, was to bring people to God. He felt that being in the right relationship with God would lead people to recover, because he believed that “alcoholism” was a consequence of a “spiritual malady”. He did modify his views somewhat in later life, but this is not reflected in the core literature, the Big Book.So we don’t have evidence that AA was ever as successful as is sometimes claimed. Rejecting the later modifications of the founders of the movement does not seem likely to bring about improvements in figures for efficacy, in light of the fact that AA was, at the outset, very religious, and religiosity is in decline throughout the world.The member profile has also changed. It was unusual when the fellowships began to find people who used drugs as well as alcohol, but since the 1980s, AA’s membership surveys have shown that around half of members have also used other drugs. While some would suggest that this has the effect of reducing group cohesion, I would tend to favour the view that this reduces the relevance of the programme to new members. The programme is meant to serve the members, not the other way round!There is also talk of the “gift of desperation” - how people increasingly join at a point where they have not “lost everything”. Research suggests that early intervention in alcohol use disorder is more likely to be successful as people have more social capital - homes, families, jobs etc - for recovery. So if it is the case that AA works best for those who have lost everything, then it is making a claim to be less effective than other treatment modalities.And treatment modalities have broadened a huge amount, alongside considerable progress in understanding alcohol use disorders. Up until the 1970s there were few alternative supports for recovery available to people in the community. This, along with his personal faith commitments, is why Dr George Vaillant continued to support AA, despite his studies repeatedly failing to show evidence of efficacy beyond that which one would expect from “natural” or “spontaneous” recovery, which runs at about 5% per year among the treatment seeking population. Any resource is considerably better than none, and companionship, advice on avoiding drinking and a way of structuring one’s time are indeed positive things to introduce to the life of anyone, particularly a “low bottom” drinker.These days there are multiple paths to recovery, many of which show strong evidence of efficacy. Secular modalities appeal to a broader range of people. The evidence does not suggest that lifelong commitment to a spiritual way of life is essential to recover from alcohol use disorder: indeed, epidemiological surveys seem to suggest that three quarters of people with the condition get better on their own without any kind of intervention, and many of them choose moderation rather than abstinence.I have no issue whatever with anyone’s personal beliefs. I am delighted to welcome recovery whatever form it takes.I have a huge issue with 12 Step treatment dominating the “rehab” industry in both the USA and Australia. A treatment that is only successful for, generously, 15% of the people who try it, is not really worthy of the name. And telling people who fail in that form of treatment to “keep coming back” really doesn’t make sense: continuing to do something that didn’t work the first time is not the normal way that treatment works. Directing people to alternative treatments that may suit them better would be more productive.AA members may point to the Traditions and say the 12 Step hegemony over treatment is an “outside issue” but in truth, AA members have been prominent lobbyists to get their treatment modality on the political agenda, and members are employed in the $35 billion dollar a year US treatment industry in large numbers. The relationship is therefore a symbiotic one.AA lacks the capacity to reform itself, because the organising principle is the will of a loving God as expressed in group conscience meetings, and the mechanisms for communicating this are slow and unwieldy. Additionally, many long term members are extremely resistant to change, arguing that what has worked well for them is in no need of reform. Others still hark back to the largely illusionary “glory days” of AA, and argue that it should become more fundamentalist, rather than more modern.AA was a wonderful idea, it challenged heavy stigma and provided real hope to many people. The forces at play today, both within and outside the fellowship, are completely different from those at work in the USA in the 1930s. Propped up by the multi billion dollar treatment industry that serves as the fellowship’s commercially orientated twelfth step department, I expect it will survive for many years to come.My belief is that the dominance of 12 Step in “rehabs” is actually leading to the unnecessary early deaths of people who would be better served by other treatment modalities. In light of this view, I believe it is well past time for AA as a whole to take a searching and fearless moral inventory of itself which includes being honest and open about its actual relationships with ASAM, the 12 Step rehab industry and other forms of political lobbying.

What percentage of depression has been solidly linked to genetic mutations (not including polymorphisms)?The cause of depression, and other emotional maladies, is a complex interplay between nature and nurture. Genetics, upbringing, culture, diet, stress levels, and epigenetics all play a role.I don't think you can put a firm number on it.Anyone can get depressed.The same might be said of “Resiliance”, our ability to resist having our internal homeostasis disturbed.Some people just seem better able to deal with the ups and downs.Certainly there are things we can do, like exercise, healthy diet, emotional counseling, medications, etc. that can help.Twin studies suggest 40% or so genetic linkage. But, this is highly contested.However, as with most attempts to find a direct genetic link to disease, there are too many variables.It's too complex for simple answers, or simple solutions.My personal take on the subject, having had my own problems with depression, is that depression is a sign of internal toxicity.Internal toxicity can come from many sources.Toxins in food, toxic drugs, toxic environment, toxic relationships, toxic work, toxic attitudes, toxic people, toxic self loathing... Some things poison your body, your mind, your spirit.The best things you can do for yourself is to remove or reduce exposure to toxic things.Figure out what is poisoning you, and get it out of your life as best you canDepression is a symptom, not a disease.Which is why I think there is no answer to this question.Here is a good starter article cribbed from pubmed:Overview of the Genetics of Major Depressive DisorderOverview of the Genetics of Major Depressive DisorderFalk W. LohoffAbstractMajor depressive disorder (MDD) is a common psychiatric illness with high levels of morbidity and mortality. Despite intensive research during the past several decades, the neurobiological basis and pathophysiology of depressive disorders remain unknown. Genetic factors play important roles in the development of MDD, as indicated by family, twin, and adoption studies, and may reveal important information about disease mechanisms. This article describes recent developments in the field of psychiatric genetics, with a focus on MDD. Early twin studies, linkage studies, and association studies are discussed. Recent findings from genome-wide association studies are reviewed and future directions discussed. Despite all efforts, thus far, no single genetic variation has been identified to increase the risk of depression substantially. Genetic variants are expected to have only small effects on overall disease risk, and multiple genetic factors in conjunction with environmental factors are likely necessary for the development of MDD. Future large-scale studies are needed to dissect this complex phenotype and to identify pathways involved in the etiology of MDD.Keywords: Depression, Mood disorder, Linkage, Association, Genetics, SNPIntroductionMajor depressive disorder (MDD) is a common psychiatric illness with high levels of morbidity and mortality. It is estimated that 10% to 15% of the general population will experience clinical depression during their lifetime [1], and 5% of men and 9% of women will experience a depressive disorder in a given year, according to the World Health Organization [2]. Genetic factors play important roles in the development of MDD, as indicated by family, twin, and adoption studies. Twin studies suggest a heritability of 40% to 50%, and family studies indicate a twofold to threefold increase in lifetime risk of developing MDD among first-degree relatives. This degree of familial aggregation, coupled with the high heritability from twin studies, generated optimism that molecular genetic techniques would reveal genes of substantial influence on MDD risk. Unfortunately, gene localization and identification has been a slow, labor-intensive process. Genetic investigators have encountered similar frustrations with other common complex traits (eg, asthma, hypertension, and diabetes mellitus).The major impediments to mood disorder gene localization and identification are as follows: 1) no single gene is necessary and sufficient for MDD; 2) each susceptibility gene contributes a small fraction of the total genetic risk; and 3) complex genetic heterogeneity, meaning that multiple partially overlapping sets of susceptibility genes (which interact with the environment) can predispose individuals to similar syndromes that are indistinguishable on clinical grounds. This article provides an overview of the current efforts to identify genetic risk factors for MDD.Twin and Family StudiesEvidence for a genetic component to mood disorders has been documented consistently using family, twin, and adoption studies. The first genetic studies of mood disorders were conducted more than 70 years ago and included assessment of concordance rates for monozygotic and dizygotic twins with mood disorders [3]. These early studies did not distinguish between bipolar depression and MDD-recurrent unipolar (MDD-RU). A recent review of twin studies in MDD-RU estimated heritability at 37%, with a substantial component of unique individual environmental risk but little shared environmental risk [4].Family studies of MDD-RU have shown that first-degree relatives of MDD-RU probands are at increased risk of MDD-RU disorders compared with first-degree relatives of control probands [5]. There was a twofold to fourfold increased risk of MDD-RU among the first-degree relatives of MDD-RU probands. Characteristics of MDD-RU disorders that yield a more heritable phenotype include early onset (ie, before age 30 years) and a high degree of recurrence. A third characteristic that may identify a separate group of disorders is the presence of psychosis. Additional genetic subtypes of MDD-RU may be identified through examination of comorbidities with panic disorder, other anxiety disorders, and alcoholism.Linkage StudiesBecause of the epidemiologic evidence for a genetic component of MDD, the field had hoped that the identification of genetic risk factors would be straightforward. The first wave of comprehensive investigations of the genetic origins of MDD used linkage studies. Linkage studies have proven to be successful in identifying genetic risk factors for rare mendelian disorders with high penetrance, such as autosomal-dominant inherited forms of epilepsy or cystic fibrosis. The term linkage refers to the observation that two genetic loci found near each other on the same chromosome tend to be inherited together more often than expected by chance within families. Two such loci are said to be linked. The key concept of linkage is that chromosomal fragments that might harbor vulnerability genes are inherited with an illness more often then expected by chance in families.Although some linkage studies in MDD have suggested several regions in the genome that might harbor risk alleles, findings have been inconsistent, and thus far, no established universal genetic risk factor or causative gene for depression has been identified. Although these initial results from linkage studies in MDD seem rather disappointing, they emphasize that MDD is a complex disorder with a complex mode of inheritance, that multiple genes with small effects likely are involved, and that identifying genetic factors is complicated by a significant gene–environment component.Several MDD linkage scans have been conducted during the past several years and are reviewed in detail elsewhere [6]; however, only a few studies had a sufficient number of affected individuals (>100). Holmans et al. [7] reported on the first phase of a multisite collaborative effort (Recurrent Early-Onset Depression [GenRED] sample). The sample consisted of 297 informative multiplex families (containing 685 informative affected relative pairs, 555 sibling pairs, and 130 other pair types). Affected cases had MDD-RU with onset before 31 years of age for probands or 41 for other affected relatives. The mean age at onset was 18.5 years, and the mean number of depressive episodes was 7.3, indicating a highly recurrent form of illness. Families were excluded if there was a first-degree or second-degree relative with bipolar disorder (BPD) [7]. Linkage was observed on chromosome 15q25.3-26.2 (empiric genome-wide P=0.023). The linkage was not sex specific. This was the sole significant linkage peak observed by this group. In the complete sample of 656 families, genome-wide suggestive linkage was confirmed on chromosome 15q and also observed on chromosomes 17p and 8p in a planned second analysis accounting for the sex of each pair of relatives [8]. Fine mapping of the 15q region demonstrated further evidence of linkage [9].Abkevich et al. [10] reported a genome scan on 110 Utah pedigrees (each with at least four affected individuals), in which there were 784 individuals with MDD-RU, 161 with single-episode MDD, and 162 with BPD who were also considered affected. They observed a highly significant linkage signal at 12q23 [10], confirming a previously identified BPD locus. No other linkage peaks approached statistical significance. It is probable that this study detected the same BPD 12q23 locus, even though the families were ascertained from an MDD-RU proband, because most kindreds probably did have at least one BPD individual. These results confirm the findings of family and twin studies suggesting genetic overlap between BPD and MDD-RU disorders, and this study identifies the 12q23 region as a locus that increases risk of both BPD and MDD-RU disorders.Camp et al. [11] reanalyzed the large Utah pedigrees and excluded relatives with BPD. They considered three alternative phenotypes (MDD age at onset earlier than 31 years of age, MDD or anxiety, MDD and anxiety) and identified regions with at least suggestive genome-wide evidence for linkage on chromosomes 3centr, 7p, and 18q [11]. Interestingly, the region identified on 18q with MDD and anxiety is also a well-replicated linkage finding in BPD.Another recent genome-wide linkage scan was carried out using 497 sibling pairs concordant for recurrent depression, excluding BPD. The advantage of affected sibling pair design is that it does not require knowledge of mode of inheritance and increased power under certain conditions. Suggestive evidence of linkage was observed on chromosomes 1p36, 12q23.3-q24.11, and 13q31.1-q31.3 [12]. The 12q locus was previously implicated in linkage studies of unipolar [10] and bipolar disorders, while the 13q peak lies within a region previously linked strongly to panic disorder [13]. Middeldorp et al. [14] used 110 Australian and 23 Dutch MDD pedigrees with at least two affected siblings. The scan identified a region on chromosome 17 that includes the gene encoding the serotonin transporter (SLC6A4). Follow-up genotyping failed to identify the previously implicated promoter length polymorphism in SLC6A4 to be associated with MDD, suggesting that another SLC6A4 variant or a polymorphism in a different gene might contribute to this signal. Interestingly, they reported chromosome 8 as their most promising finding because this region has also been implicated in two previous linkage studies of personality traits, including harm avoidance [15] and neuroticism [16]. Although linkage efforts in MDD have not identified universal risk genes yet, they have provided insights into the genomic regions that might harbor genetic susceptibility factors.Candidate Gene StudiesCandidate gene studies of unipolar depression traditionally have received less attention in the past compared with those of BPD and schizophrenia. Likely reasons for this discrepancy might be practical limitations given the much smaller expected effect size and a more heterogeneous clinical phenotype. However, with increasing sample sizes, the literature is developing rapidly. As with other complex psychiatric disorders, there is no universal susceptibility gene for MDD. It can be expected that multiple genes with small effect sizes contribute to depression. Several candidate genes show promising preliminary results and are worth mentioning. Most candidate genes are studied using a case-control association study design. The basic principle of genetic association studies is that a genetic variant(s) is investigated in a group of cases and controls. By determining the allele or genotype frequencies and comparing them statistically, the probability that a genetic polymorphism is more frequent in one group than the other can be investigated. Hypotheses are generated based on the concept that specific variants increase or decrease risk of a certain phenotype. Genetic variants for study are usually selected based on an a priorihypothesis, such as neurobiologic plausibility (eg, serotonin transporter for antidepressants) or genomic location of a candidate gene (eg, in a linkage peak). More recently, “hypothesis-free” designs have been promoted with the advance of genome-wide association studies (GWAS), which space genetic markers across the whole genome based on linkage disequilibrium patterns and are discussed later; however, the resources required to conduct GWAS, including technological and clinical resources, are considerable and remain prohibitive in many instances. It is important to note that candidate gene association studies have several limitations. Such limitations include clinical and diagnostic heterogeneity, low statistical power if sample sizes are small, often-limited biological evidence of candidate gene selection, and unknown functional relevance of tested single nucleotide polymorphisms (SNPs), as well as population stratification within the sample leading to spurious positive findings or false-negative associations. Despite these obstacles, several candidate genes deserve mention, as they have been suggested repeatedly to be implicated in MDD.Serotonin Transporter (5HTT/SLC6A4) and Serotonin Receptor 2A (HTR2A)The serotonin transporter gene and genes involved in the serotonergic system are candidate genes for susceptibility to depression given that many antidepressant medications act on these systems. Several studies have implicated the serotonin transporter gene (SLC6A4) in MDD [17–19]. A 44-bp repeat polymorphism in the promoter region of the gene (5-HTTLPR) has been shown to influence expression levels of the serotonin transporter in vitro [20], thus making this functional variant a logical candidate for investigation in MDD. This polymorphism is the most studied genetic variant in psychiatric genetics to date. Similar to candidate gene studies in other complex psychiatric disorders, there have been some positive reports and some negative findings; additional studies are needed to dissect the exact role of this gene variant in the etiology of depressive disorders [21, 22•, 23].Because the serotonin transporter gene encodes a direct target for antidepressant medications, there has been great interest in correlating genetic variation with pharmacologic treatment response [24], and the field of pharmacogenetics is rapidly developing. Results have been similarly mixed, with some studies showing a statistically significant effect of the polymorphism and others failing to do so. A recent meta-analysis of 15 published studies concluded that there was a significant association between the L allele and better treatment response to selective serotonin reuptake inhibitors [25]. Interestingly, the association between the L allele and early antidepressant treatment response was the most robust finding in this meta-analysis, suggesting that the 5-HTTLPR might predict not only treatment response but also the time course of response and remission. A recent large-scale study using DNA samples from 1,953 patients with MDD who were treated with citalopram in the Sequenced Treatment Alternatives for Depression (STAR*D) trial investigated genetic predictors of treatment response [26]. The authors could not find evidence for 5HTT variation influencing treatment response; however, they reported a significant effect with a marker in the serotonin receptor gene HTR2A and treatment outcome. As expected for a single gene, the clinical impact of HTR2A on treatment outcome is modest. Although these studies face similar complexities and obstacles as disease candidate gene studies, this pharmacogenetic approach likely will yield robust results in the near future. Case-control association studies of the serotonin receptor gene HTR2A and major depression have yielded similar mixed results as for the serotonin transporter gene [23]. The European consortium project Genome-based Therapeutic Drugs for Depression (GENDEP) recently published its initial results. This is the first large-scale, multicenter human pharmacogenomics study focused on the prediction of therapeutic response to antidepressant drugs and adverse effects [27]. This open-label, flexible-dose, multicenter trial included 760 patients with MDD who were treated with citalopram or nortriptyline for 12 weeks. Initial analysis of ten candidate genes involved in serotonin, norepinephrine, neurotrophic, and glucocorticoid signaling revealed an association between treatment response to escitalopram and several variants in the serotonin receptor gene (HTR2A), with one marker (rs9316233) explaining 1.1% of the response variance. SNPs in the norepinephrine transporter gene (SLC6A2) predicted response to nortriptyline, and variants in the glucocorticoid receptor gene (NR3C1) predicted response to both antidepressants [28]. These data further support a role for the influence of genetic variants on treatment response to antidepressant drugs. Because single-marker analysis only explains a small fraction of the variance, future studies will have to use a multiple variant approach to find clinically meaningful genetic prediction algorithms.Gene–environment interaction studies have received increasing attention, particularly for MDD, given the robust correlation between stressful life events and risk of developing depressive symptoms [17, 29]. In a population-based study, Caspi and colleagues [21] noted that individuals with one or more copies of the short allele of the 5HTT promoter variants were at increased risk of depression depending on the occurrence of adverse life events. This article describes a plausible gene–environment interaction that may help explain the conflicting results for the 5HTT promoter variant noted above. Positive and negative replication studies have demonstrated the complexity of detecting these effects. Similar gene–environment interactions have been demonstrated for variants in the HTR2A gene and childhood maternal nurturance and depressive symptoms in adulthood [30]. Future genetic studies of depression will need to pay close attention to these gene–environment interactions.Brain-Derived Neurotrophic FactorGrowing evidence suggests an important role for brain-derived neurotrophic factor (BDNF) in affective disorder [31, 32]. Preclinical animal studies have consistently documented a role of BDNF in neurogenesis [33], and animal models of depression further substantiate a role of BDNF in mood disorders. Decreased BDNF levels in the hippocampus have been reported in animals exposed to chronic stress [34]. Interestingly, administration of anti-depressants increased hippocampal BDNF, preventing the stress-induced decrease [35]. These findings are intriguing given the hippocampal volume loss observed in mood disorders and decreased BDNF serum levels in individuals with mood disorders or depressive personality traits [32]. Based on these convergent preclinical and clinical data, the BDNF gene represents a logical target for genetic investigations of mood disorders.Although there is stronger literature support for a genetic association between the Val66Met polymorphism in the BDNF gene and BPD, several studies have also investigated this SNP in MDD. Results have been similarly mixed, as with most other candidate genes for depression. Schumacher et al. [36] examined 465 individuals with MDD but did not find a significant association with the Val66Met polymorphism. However, there was evidence of a haplotypic association [36]. Surtees and colleagues [37] failed to detect an association of the Val66Met polymorphism in 1,214 individuals with a history of MDD, while studies of this polymorphism in Asian populations yielded inconsistent results. Despite these mixed and negative results, interpretation of these data should be carried out with caution given the complex structure of the gene and the fact that most studies have only investigated the Val66Met SNP. It is likely that other variation in the BDNF gene influences susceptibility to depression [38].Tryptophan HydroxylaseTryptophan hydroxylase is the rate-limiting enzyme in brain serotonin synthesis. The discovery of a new brain-specific isoform of the tryptophan hydroxylase (TPH2) has generated new interest in the connection between serotonergic systems and depression [39]. The TPH2 gene is located on chromosome 12q, a region previously implicated in linkage studies of BPD.Zill et al. [40] reported the first evidence of an association of variants in the THP2 gene and major depression. Zhang et al. [41] identified a functional polymorphism (Arg441His) that results in about 80% loss of function in serotonin production when expressed in a cell system. The authors also reported that this rare mutation was not seen in 219 healthy controls but was seen in 9 of 87 individuals with major depression [41]. However, subsequent replication attempts by other groups for this rare variant were negative. Haplotypic associations of sets of markers across the TPH2 gene have yielded positive results [42] and, interestingly, variants were associated with suicidal behavior [43, 44]. Deficits in brain serotonin synthesis secondary to genetic variation in the TPH2 gene might represent an important risk factor for unipolar depression.In light of these multiple positive and negative reports for various candidate genes, several recent meta-analyses have tried to dissect the genetic factors of depression. The hope was that by combining several underpowered small studies into one large study, the meta-analysis would have sufficient power to detect risk alleles. One of the most comprehensive meta-analyses in depression was recently published and included 183 articles covering 393 polymorphisms in 102 genes [45]. The study showed a potential role for variants in the genes APOE (apolipoprotein E), GNB3 (guanine nucleotide-binding protein β-3), MTHFR (methylene tetrahydrofolate reductase), and SLC6A4 (serotonin transporter). Lopez-Leon et al. [45] observed that the S allele of the 5-HTTLPRconferred a small increase of risk of MDD, with an OR of 1.11; however, another meta-analytic study focusing only on the 5-HTTLPRvariant recently yielded no evidence that the serotonin transporter genotype alone or in interaction with stressful life events is associated with an elevated risk of depression in men alone, women alone, or both sexes combined [22•]. Although several limitations exist in the interpretation of genetic meta-analyses (eg, publication bias and which studies are included and excluded), the overall picture is that no strong susceptibility gene or set of genetic markers for MDD could be identified.Genome-Wide Association StudiesWith the rapid development of technological advances in genomics, it is now possible to genotype 500,000 to 1 million SNPs across the genome in cases and healthy controls. This GWAS design has the advantage that no genes are preselected (as is the case in candidate gene studies), and robust findings might identify new pathways involved in mood disorders. Limitations of this approach are the immense amount of data, costs, and issues regarding multiple testing [46]. The stringent statistical correction for multiple testing might mask true signals from genes that confer only modest risk of disease [47, 48]. Currently, the genome-wide significance level is set (P<10−7to P<10−8). Despite these obstacles, the first results in complex medical disorders such as Crohn's disease, diabetes, and rheumatoid arthritis have emerged from GWAS [49], and several GWAS have been published for psychiatric disorders [50].Thus far in depression, five large GWAS have been published [51•, 52–55]. Sullivan et al. [51•] used a semi–community-based sample of 1,738 cases and 1,802 controls with MDD collected through the Genetic Association Information Network and conducted a GWAS of 435,291 SNPs. There was no genome-wide significant finding; however, they found 11 SNPs associated with MDD that are localized to a 167-kb region overlapping the gene piccolo (PCLO), a presynpatic protein also known as aczonin that is important in monoaminergic neurotransmission in the brain. A replication attempt of the initial finding failed to reach the significance threshold in five independent samples (6,079 MDD independent cases, 5,893 controls). Additional studies are needed to investigate the role of PCLO in MDD and central nervous system neurotransmission. The second published GWAS of MDD used a German clinic-based sample of 1,022 recurrent depression cases and 1,000 controls and investigated 494,678 SNPs [53]. Similar to the Sullivan et al. [51•] study, none of the SNPs were statistically significant after correction for multiple testing. The authors then performed a meta-analysis combining their first sample with a second sample of Swiss origin (494 cases, 1,052 controls) and found their best signal at rs4238010, 260 kb from the closest gene (CCND2, or cyclin D2); however, they still did not achieve genome-wide significance. Another recent GWAS of recurrent, early-onset MDD (GenRED) with onset before 31 years of age investigated 671,424 SNPs in 1,020 cases and 1,636 controls [56]. Again, no genome-wide significant evidence for association was observed. The strongest evidence for association was observed on chromosome 18q22.1 (rs17077540) in a region previously implicated in linkage scans in BPD. Recently, an additional GWAS of MDD was published that included the STAR*D sample of 1221 MDD cases [55]. In addition, the authors conducted a meta-analysis using three samples (Genetic Association Information Network, GenRED, STAR*D) with a total of 3,956 cases and 3,428 controls. There were no genome-wide significant findings in the primary analysis or any of the secondary analyses. Some intronic markers in the meta-analysis were close to genome-wide significance levels (ie, P<10−6) and included the genes ATP6V1B2, GRM7, and SP4. The SNP in the ATP6V1B2 gene is in close proximity to the adjacent gene VMAT1(vesicular monoamine transporter 1), previously implicated in BPD [56]. GRM7 encodes a cell surface receptor and might be an interesting new target for drug development. Interestingly, weak signals were also observed by Muglia et al. [53] and Sullivan and colleagues [51•] for this gene. The gene SP4 encodes a brain-specific zinc finger transcription factor, and several studies have shown an association between SP4and an SP4-binding site in GRK3 (G-protein receptor kinase 3) and BPD [57]. The most recently published GWAS of MDD by Lewis et al. [52] also failed to identify genome-wide significant genetic variants contributing to major depression. The authors included 1636 cases of depression ascertained in the United Kingdom and 1594 controls. One SNP in the BICC1 gene achieved suggestive evidence for association. A meta-analysis of United Kingdom data with previously published results from Muglia et al [53] showed some evidence for association near neuroligin-1 (NLGN1) on chromosome 3 but did not support findings at BICC1.Although the results of these five GWAS in MDD were all essentially negative, they do suggest interesting candidate genes that may be worthwhile to follow up in future studies. It is becoming increasingly clear that individual genetic susceptibility factors for depression are likely to have only minor effects, and very large pooled analyses of cases and controls will be necessary to identify them [50]. One of the first attempts of these large-scale analyses recently yielded interesting results. A meta-analysis that used GWAS data from BPD and MDD cohorts, including more than 13,600 individuals, identified six SNPs at 3p21.1 associated with major mood disorders (rs2251219; P = 3.63 × 10−8; OR, 0.87) [58•]. Supportive evidence for association was observed in two of three independent replication cohorts. These results provide an example of a shared genetic susceptibility locus for BPD and MDD and point out that perhaps our current dichotomous conceptualization of mood disorders is incorrect.Conclusions and Future DirectionsThe field of psychiatric genetics in general has been disappointing given that the initial hope to find common gene variants of large effect in the pathogenesis of mental illnesses has been unsuccessful. In most psychiatric illnesses, the phenotype seems too complex, with the patient cohorts too small, and no findings have been consistently replicated. This is also the case for MDDs. In addition, the phenotypic effects of genetic variants identified to date are weak, with ORs of 1.0 to 1.2. The picture is further complicated when comparing the magnitude of the impact of gene variation on disease susceptibility with the impact of lifestyle and environmental factors, which is likely to be large [59]. Despite these obstacles, the field of psychiatric genetics is rapidly growing, and several new technological advances (eg, whole-genome sequencing) will be soon available for large-scale studies. It is important to remember that genetic information will only provide additional information on one aspect of the complex and personal history of psychiatric patients. It is the sum of inside and outside factors that contributes and influences mental pathology and well-being.FootnotesDisclosure Dr. Lohoff reported no potential conflict of interest relevant to this article.Article informationCurr Psychiatry Rep. Author manuscript; available in PMC 2011 Dec 1.Published in final edited form as:Curr Psychiatry Rep. 2010 Dec; 12(6): 539–546.doi: 10.1007/s11920-010-0150-6PMCID: PMC3077049NIHMSID: NIHMS254781PMID: 20848240Falk W. LohoffFalk W. Lohoff, Department of Psychiatry, Translational Research Laboratory, University of Pennsylvania School of Medicine, Center for Neurobiology and Behavior, 125 South 31st Street, Room 2213, Philadelphia, PA 19104, USA;Corresponding author.Falk W. Lohoff: ude.nnepu.dem.liam@ffoholCopyright noticeThe publisher's final edited version of this article is available at Curr Psychiatry RepSee other articles in PMC that cite the published article.ReferencesPapers of particular interest, published recently, have been highlighted as:• Of importance1. Tsuang MT, Taylor L, Faraone SV. An overview of the genetics of psychotic mood disorders. J Psychiatr Res. 2004;38:3–15. [PubMed]2. Kessler RC, Chiu WT, Demler O, et al. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:617–627. [PMC free article][PubMed]3. Lohoff FW, Berrettini WH. Genetics of mood disorders. In: Charney DS, editor. 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