The Fourth Law of Behavior Genetics

Abstract

Behavior genetics is the study of the relationship between genetic variation and psychological traits. Turkheimer (2000) proposed "Three Laws of Behavior Genetics" based on empirical regularities observed in studies of twins and other kinships. On the basis of molecular studies that have measured DNA variation directly, we propose a Fourth Law of Behavior Genetics: "A typical human behavioral trait is associated with very many genetic variants, each of which accounts for a very small percentage of the behavioral variability." This law explains several consistent patterns in the results of gene discovery studies, including the failure of candidate gene studies to robustly replicate, the need for genome-wide association studies (and why such studies have a much stronger replication record), and the crucial importance of extremely large samples in these endeavors. We review the evidence in favor of the Fourth Law and discuss its implications for the design and interpretation of gene-behavior research.

Keywords: behavior genetics; genome-wide association studies; individual differences; molecular genetics; polygenic architecture.

Figure 1

Number of schizophrenia-associated SNPs clearing the strict GWAS significance threshold (p < 5×10⁻⁸) as a function of discovery-stage sample size, which has increased over time. Although the four studies presented are not methodologically identical (because of different ratios of cases to controls), the increasing number of “hits” with sample size is nevertheless informative.

Figure 2

Estimated total number of SNPs associated with five disease phenotypes based on results of genome-wide association studies (based on a figure in Ripke et al., 2013).

Figure 3

The strong agreement between genetic effects on 28 diseases estimated in Europeans and East Asians (reproduced from Marigorta & Navarro, 2013). The x-axis corresponds to the increment in the odds (on a logarithmic scale) of suffering from the disease for each additional copy of the reference allele, as estimated in Europeans. The y-axis corresponds to the same quantity estimated in East Asians. The increment in log(odds) is the equivalent of the “additive effect” for dichotomously scored traits such as disease status (affected versus unaffected). The gap in the data on the x-axis results from the fact that non-significant genetic effects would have odds ratios near 1 (and thus logarithms of 0) and therefore would not be included in the results of European samples.