TY - JOUR T1 - Ultra-rare disruptive and damaging mutations influence educational attainment in the general population JF - bioRxiv DO - 10.1101/050195 SP - 050195 AU - Andrea Ganna AU - Giulio Genovese AU - Daniel P. Howrigan AU - Andrea Byrnes AU - Mitja Kurki AU - Seyedeh M. Zekavat AU - Christopher W. Whelan AU - Mart Kals AU - Michel G. Nivard AU - Alex Bloemendal AU - Jonathan M. Bloom AU - Jacqueline I. Goldstein AU - Timothy Poterba AU - Cotton Seed AU - Robert E. Handsaker AU - Pradeep Natarajan AU - Reedik Mägi AU - Diane Gage AU - Elise B. Robinson AU - Andres Metspalu AU - Veikko Salomaa AU - Jaana Suvisaari AU - Shaun M. Purcell AU - Pamela Sklar AU - Sekar Kathiresan AU - Mark J. Daly AU - Steven A. McCarroll AU - Patrick F. Sullivan AU - Aarno Palotie AU - Tõnu Esko AU - Christina Hultman AU - Benjamin M. Neale Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/06/06/050195.abstract N2 - 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 ER -