RT Journal Article
SR Electronic
T1 Identifying genetic variants that affect viability in large cohorts
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 085969
DO 10.1101/085969
A1 Hakhamanesh Mostafavi
A1 Tomaz Berisa
A1 Felix R Day
A1 John R B Perry
A1 Molly Przeworski
A1 Joseph K Pickrell
YR 2017
UL http://biorxiv.org/content/early/2017/06/19/085969.abstract
AB A number of open questions in human evolutionary genetics would become tractable if we were able to directly measure evolutionary fitness. As a step towards this goal, we developed a method to examine whether individual genetic variants, or sets of genetic variants, currently influence viability. The approach consists in testing whether the frequency of an allele varies across ages, accounting for variation in ancestry. We applied it to the Genetic Epidemiology Research on Aging (GERA) cohort and to the parents of participants in the UK Biobank. Across the genome, we find only a few common variants with large effects on age-specific mortality: tagging the APOE ε4 allele and near CHRNA3. These results suggest that when large, even late onset effects are kept at low frequency by purifying selection. Testing viability effects of sets of genetic variants that jointly influence one of 42 traits, we detect a number of strong signals. In participants of the UK Biobank study of British ancestry, we find that variants that delay puberty timing are enriched in longer-lived parents (P~6×10−6 for fathers and P~2×10−3 for mothers), consistent with epidemiological studies. Similarly, in mothers, variants associated with later age at first birth are associated with a longer lifespan (P~1×10−3). Signals are also observed for variants influencing cholesterol levels, risk of coronary artery disease, body mass index, as well as risk of asthma. These signals exhibit consistent effects in the GERA cohort and among participants of the UK Biobank of non-British ancestry. Moreover, we see marked differences between males and females, most notably at the CHRNA3 locus, and variants associated with risk of coronary artery disease and cholesterol levels. Beyond our findings, the analysis serves as a proof of principle for how upcoming biomedical datasets can be used to learn about selection effects in contemporary humans.