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

doi:10.1038/nn.4404

. 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 Nivard¹⁰, 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 Mägi⁸, Diane Gage³, Elise B Robinson^{1

2

3}, Andres Metspalu⁸, Veikko Salomaa¹¹, Jaana Suvisaari¹¹, 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 Hultman⁴, Benjamin M Neale^{1

2

3}

Affiliations

¹ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston 02114, MA, USA.
² Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁴ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 171 77, Sweden.
⁵ Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
⁶ Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki FI-00014, Finland.
⁷ Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, 02114, USA.
⁸ Estonian Genome Center, University of Tartu, Tartu 51010, Estonia.
⁹ Institute of Mathematics and Statistics, University of Tartu, Tartu 50409, Estonia.
¹⁰ Department of Biological Psychology, VU University Amsterdam, Amsterdam 1081 HV, The Netherlands.
¹¹ Department of Health, THL-National Institute for Health and Welfare, Helsinki FI-00271, Finland.
¹² Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
¹³ Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
¹⁴ Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, North Carolina 27599-7264, USA.

^# Contributed equally.

PMID: 27694993
PMCID: PMC5127781
DOI: 10.1038/nn.4404

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

Andrea Ganna et al. Nat Neurosci. 2016 Dec.

. 2016 Dec;19(12):1563-1565.

doi: 10.1038/nn.4404. Epub 2016 Oct 3.

Authors

Affiliations

¹ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston 02114, MA, USA.
² Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁴ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 171 77, Sweden.
⁵ Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
⁶ Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki FI-00014, Finland.
⁷ Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, 02114, USA.
⁸ Estonian Genome Center, University of Tartu, Tartu 51010, Estonia.
⁹ Institute of Mathematics and Statistics, University of Tartu, Tartu 50409, Estonia.
¹⁰ Department of Biological Psychology, VU University Amsterdam, Amsterdam 1081 HV, The Netherlands.
¹¹ Department of Health, THL-National Institute for Health and Welfare, Helsinki FI-00271, Finland.
¹² Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
¹³ Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
¹⁴ Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, North Carolina 27599-7264, USA.

^# Contributed equally.

PMID: 27694993
PMCID: PMC5127781
DOI: 10.1038/nn.4404

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**
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**
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**
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.

See this image and copyright information in PMC

Comment in

Rare mutations and educational attainment.
Cesarini D. Cesarini D. Nat Neurosci. 2016 Nov 29;19(12):1538-1539. doi: 10.1038/nn.4445. Nat Neurosci. 2016. PMID: 27898085 No abstract available.

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[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.

[2] 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.

[3] Haveman R, Wolfe B. The Determinants of Children's Attainments: A Review of Methods and Findings. Journal of Economic Literature. 1995;33:1829–1878.

[4] Haveman R, Wolfe B. The Determinants of Children's Attainments: A Review of Methods and Findings. Journal of Economic Literature. 1995;33:1829–1878.

[5] 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

[6] 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

[7] Cutler DM, Lleras-Muney A. Education and Health: Evaluating Theories and Evidence. National Bureau of Economic Research Working Paper Series No. 12352. 2006

[8] Cutler DM, Lleras-Muney A. Education and Health: Evaluating Theories and Evidence. National Bureau of Economic Research Working Paper Series No. 12352. 2006

[9] Okbay A, et al. Genome-wide association study identifies 74 loci associated with educational attainment. Nature advance online publication. 2016 - PMC - PubMed

[10] Okbay A, et al. Genome-wide association study identifies 74 loci associated with educational attainment. Nature advance online publication. 2016 - PMC - PubMed

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

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

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