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Thursday, September 4, 2014

Genetics or Environment? Why Two New Landmark Studies May Change Your Mind

Genetics or Environment? Why Two New Landmark Studies May Change Your Mind

by Charles Raison, MD

My close friend and fellow Psych Congress Steering Committee member Rakesh Jain, MD, has been riding high lately. He and I have an ongoing friendly, but intense, debate about the relative importance of genetic versus environmental factors in the etiology of psychiatric disease. He is a hardcore genetic determinist, convinced that eventually all mental illness will be shown to derive from our genes. While I certainly recognize the power of genes, I maintain that environmental factors play a far larger role in the pathogenesis of mental illness than the good Dr. Jain would ever allow.

Lately science appears to have been favoring Dr. Jain’s position, something he has noted in repeated gleeful emails to me over last month. In particular, two landmark studies have shown conclusively that genes play a definite role in the risk for major mental illness, in this case schizophrenia and autism. Using very large sample sizes and complex, high-tech analytic methods, one of these studies reports that approximately 60% of the risk for autism comes from our genes and the other finds that 108 single nucleotide polymorphisms (SNPs) contribute significantly to the risk for schizophrenia.[1,2]

I say these studies appear to favor Dr. Jain’s position because they establish definitively that genes play a major, and perhaps the major, role in risk for two of our most serious mental illnesses. But as an “environmentalist” I could not have been more thrilled by the study results.

I want to suggest that these two recent studies are game changers for psychiatry not because they demonstrate the primacy of genes, but because of what kind of genetic changes they find to be most important for disease risk. Specifically, the genes that most powerfully increase the risk for schizophrenia and autism point straight back to the environment.

To understand how this can be the case, we have to step back a bit from the details and quickly visit what I think is the primary debate within psychiatric genetics. The crux of this debate boils down to the question of whether serious mental illnesses are more likely to be caused by rare mutations that have large effects or very common forms of genes that individually have very small effects but that together add up to produce disease. [3]

The results from the recent studies in autism and schizophrenia are unequivocal: these diseases are mostly caused by the combination of many common SNPs, any one of which has only a minor effect. Although rare mutations may have huge effects in any given individual (say someone born with a new deleterious mutation), their overall contribution to disease burden is small, for example 2.6% of the genetic risk for autism.

It is apparent both from data and common sense observations that both schizophrenia and autism reduce Darwinian fitness, meaning that afflicted individuals are less likely to leave viable offspring to pass along the genes that promote these disorders. It turns out this simple fact has huge implications, because it immediately raises the question of why genes that contribute to these catastrophic conditions should have been retained in the human gene pool.

There are only two possible answers to this question. One is that although autism and schizophrenia are common, the genes that cause them are not. In this scenario, these diseases result from any of a large number of different rare, and highly deleterious, mutations. These mutations occur, cause the disease, and then vanish when the afflicted individual fails to reproduce, only to reappear “de novo” in other individuals where they suffer the same fate. However, although many subtly different rare mutations exist and cause the disease states we now recognize as schizophrenia or autism, any one of these “killer” mutations must be rare—in general never existing in more than 1% of the population.

But this possibility is essentially dismissed by the recent studies. Rather than being caused by rare but very powerful mutations, schizophrenia and autism are far more often caused by the summed total effects of many different very common forms of genes. And here is where the environment comes roaring back in.

Any given form of a gene (i.e. a SNP) can only be common if it is interacting with the environment (or did so in the past) in ways that had a survival and/or reproductive benefit. Genes that are wholly deleterious never exist at rates higher than about 1% of the population because they are quickly culled by natural selection from the gene pool.

This means that while schizophrenia and autism are manifestly not good for survival or reproduction, the genes that cause the illnesses are, or were, of some benefit across most of human history. Indeed the genetic risk factors for schizophrenia and autism are common because they must confer benefit, but are not ubiquitous because these benefits come at a cost, a phenomenon known as balancing selection. [4]

The key point is that the genes for schizophrenia and autism are not “bad”. They are not errors like the ones that cause rare genetic diseases. They are genes that the environment has actively selected as being of value. In this way these genes can be seen as the residues of our species’ long history of interactions with past environments. In a way, these genes are past environments, crystalized now within the structure of our DNA.

So what benefits could possibly explain how common each of these risk SNPs (or alleles) is in modern populations?

Again, the answer boils down to two general, non-exclusive possibilities. One possibility is that the symptoms of the diseases themselves are of some survival or reproductive benefit. Or, more likely, that conditions such as schizophrenia and autism represent the extreme end of continuous traits that enhance fitness when present to a lesser degree. This is the most common argument advanced by those seeking to account for the high prevalence of risk alleles, and much evidence supports this possibility. To take just one example among many, a recent study found that children with autistic spectrum disorders had substantially better motion perception (something of potential survival relevance in ancestral environments) when compared to normal children. [5]

A second possibility that might account for the high prevalence of risk alleles for psychiatric conditions goes by the technical name of pleiotropy, which means that the same gene can have a multitude of different biological/behavioral effects, some of which—like promoting schizophrenia and autism—may be deleterious to survival, while having other effects that might promote fitness. The prevalence of any given SNP in human populations then reflects to a large degree the balance of these costs and benefits.

This is the tack my research group has taken in most of our work exploring evolutionary factors that drive the development and maintenance of genes for psychiatric disorders. In particular, we have argued that genes that promote depression in particular may have evolved because they enhanced our ability to survive infections in the long eons before modern sanitation, refrigeration, public health education, and medicine did much of this job for us. [6]

Interestingly, the evidence for a link between immune function and disease is even stronger for schizophrenia and autism than for depression. For example, of the 108 SNPs associated with schizophrenia, most of them fall into two main camps. Many are linked to signaling in the central nervous system. Many of the others are, remarkably, found in genes that regulate the immune system.

So how would an “environmentalist” summarize the recent findings in autism and schizophrenia?

First and most importantly, the genetic alleles most relevant to these disorders are not “bad genes”. They exist because of their benefit in prior environments. This complicates any simple ideas that gene therapy will ever be a simple cure for disorders such as schizophrenia or autism (and even less so for depression). In the first place, for most individuals with the disorders, any specific SNP will only contribute a miniscule amount of the risk. Second, if the genetic variation that increases the risk for mental illness is stripped from the human genome we will likely be leaving ourselves less adapted as a species to the world in which we live.

The second point an environmentalist would take from the recent findings is that genes and environment are like the yin and yang of traditional Chinese thinking—really separate sides of the same complex coin.

Genes only exist as responses that have worked to prior environments or as genuine worthless flubs. Some cases of autism and schizophrenia result from flubs, from simple mistakes. The majority result from forms of genes that have been endorsed by the environment to various degrees as winning strategies for what it means to be human.


1. Gaugler T, Klei L, Sanders SJ, et al. Most genetic risk for autism resides with common variation. Nat Genet. Aug 2014;46(8):881-885.

2. Schizophrenia Working Group of the Psychiatric Genomics C. Biological insights from 108 schizophrenia-associated genetic loci. Nature. Jul 24 2014;511(7510):421-427.

3. International HapMap C, Altshuler DM, Gibbs RA, et al. Integrating common and rare genetic variation in diverse human populations. Nature. Sep 2 2010;467(7311):52-58.

4. Turelli M, Barton NH. Polygenic variation maintained by balancing selection: pleiotropy, sex-dependent allelic effects and G x E interactions. Genetics. Feb 2004;166(2):1053-1079.

5. Foss-Feig JH, Tadin D, Schauder KB, Cascio CJ. A substantial and unexpected enhancement of motion perception in autism. J Neurosci. May 8 2013;33(19):8243-8249.

6. Raison CL, Miller AH. The evolutionary significance of depression in pathogen host defense (PATHOS-D). Molecular Psychiatry. 2012;Epub.

Charles L. Raison, MD, is an associate professor in the Department of Psychiatry, College of Medicine and the Barry and Janet Lang Associate Professor of Integrative Mental Health in the Norton School of Family and Consumer Sciences, College of Agriculture and Life Sciences, University of Arizona, Tucson, AZ. He is also the behavioral health expert for, and he is a Psych Congress Steering Committee member.

The views expressed on this blog are solely those of the blog post author and do not necessarily reflect the views of Psych Congress Network or other Psych Congress Network authors.

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