Extreme Polygenicity of Complex Traits Is Explained by Negative Selection

Genome-wide association studies (GWAS) have shown that human complex diseases (e.g. type-2 diabetes, bipolar disorder, obesity) and multifactorial traits (e.g. height, drug response, response to environmental toxicants) are heritable and highly polygenic (i.e. caused by contributions from many genes). Usually, there are no “large-effect” common single-nucleotide variants (SNVs), and heritability appears to be evenly spread across thousands of small-effect SNVs. This polygenic distribution of heritability presents a challenge, because small-effect SNVs are difficult to detect and difficult to interpret. [Because these small-effect SNVs are difficult to detect — the term, ‘‘missing heritability’’ has been proposed to describe this dilemma.]

One factor contributing to the polygenic distribution of heritability is the complexity of the underlying biology: many genes and regions of the genome, if mutated, have a “non-zero” (i.e. extremely small, but not zero) phenotypic effect. A plausible explanation for this large mutational target is that cellular networks are densely interconnected, such that nearly every gene expressed in a relevant cell-type has a small phenotypic effect “somewhere”. Redundancy also is present (i.e. mutation or ablation of one gene often invokes other genes to compensate for that loss).

Although biological complexity clearly contributes to the polygenicity of complex traits, negative selection may also be a critical factor [In these GEITP pages recently, please recall that: during evolution of a species, ‘positive selection’ means accepting new mutations (SNVs) that benefit survival (ability to find food, reproduce, and avoid predators), whereas ‘purifying (or negative) selection’ is the default process of ‘elimination of the unfit’, i.e. SNVs are ‘tolerated’ only if they do not confer a significant disadvantage to survival of the species]. Biological complexity determines the effect-size distribution of new mutations. Authors [see attached article] postulated that, for most complex traits, relatively few genes and loci are critical, and negative selection — purging large-effect mutations in these regions — leaves behind common-variant associations in thousands of less critical regions instead; authors refer to this phenomenon as flattening.

To quantify the effects of flattening, authors introduced a mathematical definition of polygenicity, the effective number of independently associated SNVs — which describes how evenly the heritability of a trait is spread across the genome. Analyzing 33 complex traits, authors determined that heritability is spread about four times more evenly among common SNVs than among low-frequency SNVs. This difference, together with evolutionary modeling of new mutations, suggests that complex traits would be orders of magnitude less polygenic, were it not for the influence of negative selection. These results also suggest that (for most multifactorial traits) the genes and loci having the most critical biological effects — often differ from those with the strongest common-variant associations. 😊


Am J Hum Genet 5 Sept 2019; 105: 456–476

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