Pedigree- and SNP-Associated Genetics and Recent Environment are the Major Contributors to Anthropometric and Cardiometabolic Trait Variation

Genome-wide association studies have successfully identified thousands of loci for a range of human complex traits and diseases. The proportion of phenotypic variance explained by significant associations is, however, limited. Given the same dense SNP panels, mixed model analyses capture a greater proportion of phenotypic variance than single SNP analyses but the total is generally still less than the genetic variance estimated from pedigree studies. Combining information from pedigree relationships and SNPs, we examined 16 complex anthropometric and cardiometabolic traits in a Scottish family-based cohort comprising up to 20,000 individuals genotyped for ~520,000 common autosomal SNPs. The inclusion of related individuals provides the opportunity to also estimate the genetic variance associated with pedigree as well as the effects of common family environment. Trait variation was partitioned into SNP-associated and pedigree-associated genetic variation, shared nuclear family environment, shared couple (partner) environment and shared full-sibling environment. Results demonstrate that trait heritabilities vary widely but, on average across traits, SNP-associated and pedigree-associated genetic effects each explain around half the genetic variance. For most traits the recently-shared environment of couples is also significant, accounting for ~11% of the phenotypic variance on average. On the other hand, the environment shared largely in the past by members of a nuclear family or by full-siblings, has a more limited impact. Our findings point to appropriate models to use in future studies as pedigree-associated genetic effects and couple environmental effects have seldom been taken into account in genotype-based analyses. Appropriate description of the trait variation could help understand causes of intra-individual variation and in the detection of contributing loci and environmental factors.Author Summary: Unravelling overall trait architecture of complex traits and diseases is important for phenotype prediction and disease prevention and correct modelling of the trait will further aid discovery of causative loci. Here we take advantage of genome-wide data and a large family-based study to examine the role of common genetic variants, pedigree-associated genetic variants, shared family environment, shared couple environment and shared sibling environment on 16 anthropometric and cardiometabolic traits. By analysing up to ~20,000 Scottish individuals, we find that common genetic variants, pedigree-associated genetic variants and recently-shared environment of couples are the most important contributors to variation in these traits, while past family and sibling environment have a limited impact. Further studies on the pedigree-associated genetic variation and the shared couple environment effect are needed, as little research has been devoted to them so far.