This paper is not about schizophrenia, but holds lessons for those interested in the oft-debated genetic architecture of complex traits.

There are now substantial data that schizophrenia is highly polygenic (Purcell et al., 2009 and Ripke et al., 2011)—hundreds and perhaps thousands of different genetic variants at different places in the genome each contribute a small portion of risk. Indeed, such loci account for a substantial portion of the variance in liability to schizophrenia, on the order of 25-33 percent (Ripke et al., 2011 and Lee et al., 2012), a substantial fraction of the heritability of schizophrenia (65-81 percent; Sullivan et al., 2003 and Lichtenstein et al., 2009).

Two large studies have shown that human height and body mass are also highly polygenic. Other studies have...  Read more

This paper is not about schizophrenia, but holds lessons for those interested in the oft-debated genetic architecture of complex traits.

There are now substantial data that schizophrenia is highly polygenic (Purcell et al., 2009 and Ripke et al., 2011)—hundreds and perhaps thousands of different genetic variants at different places in the genome each contribute a small portion of risk. Indeed, such loci account for a substantial portion of the variance in liability to schizophrenia, on the order of 25-33 percent (Ripke et al., 2011 and Lee et al., 2012), a substantial fraction of the heritability of schizophrenia (65-81 percent; Sullivan et al., 2003 and Lichtenstein et al., 2009).

Two large studies have shown that human height and body mass are also highly polygenic. Other studies have found many robust and replicable loci for inflammatory bowel disease (>100) and type 2 diabetes mellitus (>30). However, few studies have evaluated the upper bounds of polygenicity.

In this informative and important paper by Stahl et al., the authors evaluated the genetic architectures of rheumatoid arthritis, celiac disease, MI/coronary artery disease, and type 2 diabetes mellitus. In each instance, the results were roughly similar to those for schizophrenia. The genetic architectures of these diseases mainly consist of small contributions to risk from thousands of different genetic loci. These loci, from an imperfect generation of genotyping chips, account for a sizable fraction of variance in liability. And, as has been shown for schizophrenia (Lee et al., 2012), so-called "synthetic associations" cannot explain the findings.

These data taken together now strongly support the idea that polygenicity is the hallmark of complex traits. It will be interesting to see if there are complex diseases for which this model does not hold (e.g., autism). But, for most diseases, polygenicity seems to be a fact of life, and the way that nature dealt the cards.

References:

Purcell SM, Wray NR, Stone JL, Visscher PM, O'Donovan MC, Sullivan PF, Sklar P. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature . 2009 Aug 6 ; 460(7256):748-52. Abstract

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Lee SH, Decandia TR, Ripke S, Yang J, Sullivan PF, Goddard ME, Keller MC, Visscher PM, Wray NR. Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs. Nat Genet . 2012 ; 44(3):247-250. Abstract

Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry . 2003 Dec ; 60(12):1187-92. Abstract

Lichtenstein P, Yip BH, Björk C, Pawitan Y, Cannon TD, Sullivan PF, Hultman CM. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet . 2009 Jan 17 ; 373(9659):234-9. Abstract