Overview:
We analysed whole-genome sequence (WGS) data from 347,630 European ancestry individuals in the UK Biobank to quantify the relative contribution of 40 million single nucleotide and short indel variants (with a minor allele frequency (MAF) larger than 0.01%) to the heritability of 34 complex traits and diseases. We further mapped the rare-variant heritability to single-loci associations through GWAS-by-WGS.
Methods:
We selected 34 complex phenotypes spanning a wide range of human traits and common diseases and showing a marginally significant estimate of from 171,446 pairs of relatives in the UKB, a significant ) and a marginally significant rare-variant heritability estimate (P<0.05). We then estimated for these 34 traits using the GREML-LDMS method implemented in MPH v0.53.217. We performed additional sensitivity analyses of the effect on of varying the number of PCs and birthplace clusters fitted as fixed effects. Finally, we performed GWAS on ~450,000 samples in the UKB and highlighted the main characteristics specific to rare-variants associations.
Results:
On average across phenotypes, we find that WGS captures approximately 88% of the pedigree-based narrow sense heritability, that is 20% from rare variants and 68% from common variants. We identified 15 traits with no significant difference between WGS-based and pedigree-based heritability estimates, suggesting their heritability is fully accounted for by WGS data, with an important contribution from non-coding rare variants. The GWAS analyses of all 34 phenotypes identified 11,243 common-variant associations and 886 rare-variant associations and evidenced a strong colocalization between common and rare variants signals, located near genic regions. For lipid traits, >25% of rare-variant heritability can be mapped to specific loci from GWAS in the UKBiobank.