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. 2016 Dec;19(12):1563-1565.
doi: 10.1038/nn.4404. Epub 2016 Oct 3.

Ultra-rare disruptive and damaging mutations influence educational attainment in the general population

Andrea Ganna #  1   2   3   4 , Giulio Genovese #  2   3   5 , Daniel P Howrigan  1   2   3 , Andrea Byrnes  1   2   3 , Mitja Kurki  1   2   3   6 , Seyedeh M Zekavat  2   7 , Christopher W Whelan  2   3   5 , Mart Kals  8   9 , Michel G Nivard  10 , Alex Bloemendal  1   2   3 , Jonathan M Bloom  1   2   3 , Jacqueline I Goldstein  1   2   3 , Timothy Poterba  1   2   3 , Cotton Seed  1   2   3 , Robert E Handsaker  2   3   5 , Pradeep Natarajan  2   7 , Reedik Mägi  8 , Diane Gage  3 , Elise B Robinson  1   2   3 , Andres Metspalu  8 , Veikko Salomaa  11 , Jaana Suvisaari  11 , Shaun M Purcell  12   13 , Pamela Sklar  12   13 , Sekar Kathiresan  2   7 , Mark J Daly  1   2   3 , Steven A McCarroll  2   3   5 , Patrick F Sullivan  4   14 , Aarno Palotie  1   3   6 , Tõnu Esko  2   8 , Christina Hultman  4 , Benjamin M Neale  1   2   3
Affiliations

Ultra-rare disruptive and damaging mutations influence educational attainment in the general population

Andrea Ganna et al. Nat Neurosci. 2016 Dec.

Abstract

Disruptive, damaging ultra-rare variants in highly constrained genes are enriched in individuals with neurodevelopmental disorders. In the general population, this class of variants was associated with a decrease in years of education (YOE). This effect was stronger among highly brain-expressed genes and explained more YOE variance than pathogenic copy number variation but less than common variants. Disruptive, damaging ultra-rare variants in highly constrained genes influence the determinants of YOE in the general population.

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Figures

Figure 1
Figure 1
Association between number of disruptive, damaging, and synonymous URVs in HC genes and YOE. Disruptive and damaging, but not synonymous URVs are significantly associated with reduced YOE. The size of the squares is proportional to the size of the study. The horizontal bars represent 95% confidence intervals. All the estimates are obtained from a linear regression model. Meta-analysis results are obtained using a fixed-effect approach.
Figure 2
Figure 2
Association between numbers of disruptive, damaging and synonymous URVs for different gene sets. The intersection between HC and brain-expressed genes yield the strongest reduction in YOE. We only report the meta-analysis results (N=14,133). The horizontal bars represent 95% confidence intervals. All the estimates are obtained from a linear regression model and combined using fixed-effect meta-analysis.
Figure 3
Figure 3
Association between each of the normalized scores (polygenic, runs of homozygosity, URVs and pathogenic CNVs) and YOE. The results presented are from meta-analysis of Swedish WES, Estonian WGS and Finnish WGS studies (N=13,353), except for the polygenic score, which is calculated only in the Swedish WES study (N=10,651). Notice that we plot 1-polygenic score to obtain a negative association with YOE. The horizontal bars represent 95% confidence intervals. All the estimates are obtained from a linear regression model and combined using fixed-effect meta-analysis.
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References

    1. McLendon MK, Perna LW. State Policies and Higher Education Attainment. The ANNALS of the American Academy of Political and Social Science. 2014;655:6–15.
    1. Haveman R, Wolfe B. The Determinants of Children's Attainments: A Review of Methods and Findings. Journal of Economic Literature. 1995;33:1829–1878.
    1. Krapohl E, et al. The high heritability of educational achievement reflects many genetically influenced traits, not just intelligence. Proc Natl Acad Sci U S A. 2014;111:15273–8. - PMC - PubMed
    1. Cutler DM, Lleras-Muney A. Education and Health: Evaluating Theories and Evidence. National Bureau of Economic Research Working Paper Series No. 12352. 2006
    1. Okbay A, et al. Genome-wide association study identifies 74 loci associated with educational attainment. Nature advance online publication. 2016 - PMC - PubMed

METHODS-ONLY REFERENCES

    1. Ripke S, et al. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet. 2013;45:1150–9. - PMC - PubMed
    1. Leitsalu L, et al. Cohort Profile: Estonian Biobank of the Estonian Genome Center, University of Tartu. Int J Epidemiol. 2015;44:1137–47. - PubMed
    1. Vartiainen E, et al. Thirty-five-year trends in cardiovascular risk factors in Finland. Int J Epidemiol. 2010;39:504–18. - PubMed
    1. Jostins L, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491:119–24. - PMC - PubMed
    1. Schizophrenia Working Group of the Psychiatric Genomics, C. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–7. - PMC - PubMed

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