Contribution of rare whole-genome sequencing variants to plasma protein levels and the missing heritability

• Despite the success of genome-wide association studies, much of the genetic contribution to complex traits remains unexplained. Here, we analysed high coverage whole genome sequencing data, to evaluate the contribution of rare genetic variants to 414 plasma proteins. The frequency distribution of genetic variants was skewed towards the rare spectrum, and damaging variants were more often rare. We estimated that less than 4.3% of the narrow-sense heritability is expected to be explained by rare variants in our cohort. Using a gene-based approach, we identified Cis-associations for 237 of the proteins, which is slightly more compared to a GWAS (N=213), and we identified 34 loci in Trans. Several associations were driven by rare variants, and rare variants had on average larger phenotypic effects. We conclude therefore that rare variants could be of  importance for precision medicine applications, but have a more limited contribution to the missing heritability of complex diseases.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medical Genetics (hsv//eng)

Keyword

Rare variants

SKAT

Protein Biomarkers

Hidden heritability

Missing heritability

GWAS

Publication and Content Type

ref (subject category)

art (subject category)