RT Journal Article
SR Electronic
T1 Ultra-rare disruptive and damaging mutations influence educational attainment in the general population
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 050195
DO 10.1101/050195
A1 Andrea Ganna
A1 Giulio Genovese
A1 Daniel P. Howrigan
A1 Andrea Byrnes
A1 Mitja Kurki
A1 Seyedeh M. Zekavat
A1 Christopher W. Whelan
A1 Mart Kals
A1 Michel G. Nivard
A1 Alex Bloemendal
A1 Jonathan M. Bloom
A1 Jacqueline I. Goldstein
A1 Timothy Poterba
A1 Cotton Seed
A1 Robert E. Handsaker
A1 Pradeep Natarajan
A1 Reedik Mägi
A1 Diane Gage
A1 Elise B. Robinson
A1 Andres Metspalu
A1 Veikko Salomaa
A1 Jaana Suvisaari
A1 Shaun M. Purcell
A1 Pamela Sklar
A1 Sekar Kathiresan
A1 Mark J. Daly
A1 Steven A. McCarroll
A1 Patrick F. Sullivan
A1 Aarno Palotie
A1 Tõnu Esko
A1 Christina Hultman
A1 Benjamin M. Neale
YR 2016
UL http://biorxiv.org/content/early/2016/06/06/050195.abstract
AB Ultra-rare inherited and de novo disruptive variants in highly constrained (HC) genes are enriched in neurodevelopmental disorders 1–5. However, their impact on cognition in the general population has not been explored. We hypothesize that disruptive and damaging ultra-rare variants (URVs) in HC genes not only confer risk to neurodevelopmental disorders, but also influence general cognitive abilities measured indirectly by years of education (YOE). We tested this hypothesis in 14,133 individuals with whole exome or genome sequencing data. The presence of one or more URVs was associated with a decrease in YOE (3.1 months less for each additional mutation; P-value=3.3×10−8) and the effect was stronger in HC genes enriched for brain expression (6.5 months less, P-value=3.4×10−5). The effect of these variants was more pronounced than the estimated effects of runs of homozygosity and pathogenic copy number variation 6–9. Our findings suggest that effects of URVs in HC genes are not confined to severe neurodevelopmental disorder, but influence the cognitive spectrum in the general population