%0 Journal Article %A Andrea Ganna %A Giulio Genovese %A Daniel P. Howrigan %A Andrea Byrnes %A Mitja Kurki %A Seyedeh M. Zekavat %A Christopher W. Whelan %A Mart Kals %A Michel G. Nivard %A Alex Bloemendal %A Jonathan M. Bloom %A Jacqueline I. Goldstein %A Timothy Poterba %A Cotton Seed %A Robert E. Handsaker %A Pradeep Natarajan %A Reedik Mägi %A Diane Gage %A Elise B. Robinson %A Andres Metspalu %A Veikko Salomaa %A Jaana Suvisaari %A Shaun M. Purcell %A Pamela Sklar %A Sekar Kathiresan %A Mark J. Daly %A Steven A. McCarroll %A Patrick F. Sullivan %A Aarno Palotie %A Tõnu Esko %A Christina Hultman %A Benjamin M. Neale %T Ultra-rare disruptive and damaging mutations influence educational attainment in the general population %D 2016 %R 10.1101/050195 %J bioRxiv %P 050195 %X 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 %U https://www.biorxiv.org/content/biorxiv/early/2016/06/06/050195.full.pdf