Multifactorial traits are phenotypes –– having hundreds, perhaps thousands, of genes plus epigenetic effects plus environmental factors –– ALL contributing to the trait. A multifactorial trait can be height, weight, autism spectrum disorder (ASD), attention-deficit hydractivity disorder (ADHD), mental depression, obesity, type-2 diabetes, or a type of cancer. Many drug responses (efficacy, dose-independent adverse reactions) and individual responses to environmental toxicants (i.e. “environmental diseases”) also fall into this category.
Height is a highly heritable, classic polygenic trait that is easy to recruit large cohort sizes –– much easier than trying to recruit large samples of patients on a particular dose of a particular drug..!! In the largest previous study until now, 697 independent variants (single-nucleotide polymorphisms; SNPs; or variants; SNVs) –– located within 423 loci were identified in a large genome-wide association study (GWAS) that together explained around 20% of the heritability of height [Wood et al. Nat Genet 2o14].
In the attached article, authors [using whole-exome sequencing (WES) methodology] studied a discovery sample of 458,927 individuals, and then validated their GWAS results in an independent set of 252,501 participants; this is a total cohort size of N = 711,428. They found an additional 83 height-associated coding variants having lower minor-allele frequencies (in the range of 0.1–4.8%) and effects of up to 2 centimeters per allele –– greater than ten times the average effect of common variants. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. These variants implicate relevant genes and pathways.
Interestingly, in combination, these 83 rare and low-frequency newly-identified variants explained an additional 1.7% of the heritability of height. Thus, there still remains about 78% of height heritability yet to be explained –– even after scientists have identified 697+83 = 780 variants..!! These data demonstrate that increasing sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes.
This study also supports the “infinitesimal model “, a classic model for polygenic traits –– first introduced by Fisher (1918); this model assumes a very large number of genetic loci, each with an infinitesimally small-effect. Those loci detected by GWAS are simply those having the largest effect-sizes (i.e. “low hanging fruit”). These results are consistent with the problems in predicting individual responses to many drugs and environmnetal toxicants: “even if these small-effect variants can be detected in large cohorts, they will never have clinical utility in PREDICTING any individual’s response.” 🙁
Nature 9 Feb 2o17; 542: 186–190