Ultra-rare disruptive and damaging mutations influence educational attainment in the general population.
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.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston 02114, MA, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 171 77, Sweden.
Andrea
A
Ganna
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Giulio
G
Genovese
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston 02114, MA, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Daniel P
DP
Howrigan
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston 02114, MA, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Andrea
A
Byrnes
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston 02114, MA, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki FI-00014, Finland.
Mitja
M
Kurki
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, 02114, USA.
Seyedeh M
SM
Zekavat
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Christopher W
CW
Whelan
Estonian Genome Center, University of Tartu, Tartu 51010, Estonia.|Institute of Mathematics and Statistics, University of Tartu, Tartu 50409, Estonia.
Mart
M
Kals
Department of Biological Psychology, VU University Amsterdam, Amsterdam 1081 HV, The Netherlands.
Michel G
MG
Nivard
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston 02114, MA, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Alex
A
Bloemendal
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston 02114, MA, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Jonathan M
JM
Bloom
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston 02114, MA, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Jacqueline I
JI
Goldstein
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston 02114, MA, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Timothy
T
Poterba
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston 02114, MA, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Cotton
C
Seed
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Robert E
RE
Handsaker
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, 02114, USA.
Pradeep
P
Natarajan
Estonian Genome Center, University of Tartu, Tartu 51010, Estonia.
Reedik
R
Mägi
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Diane
D
Gage
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston 02114, MA, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Elise B
EB
Robinson
Estonian Genome Center, University of Tartu, Tartu 51010, Estonia.
Andres
A
Metspalu
Department of Health, THL-National Institute for Health and Welfare, Helsinki FI-00271, Finland.
Veikko
V
Salomaa
Department of Health, THL-National Institute for Health and Welfare, Helsinki FI-00271, Finland.
Jaana
J
Suvisaari
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Shaun M
SM
Purcell
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Pamela
P
Sklar
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, 02114, USA.
Sekar
S
Kathiresan
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston 02114, MA, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Mark J
MJ
Daly
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Steven A
SA
McCarroll
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 171 77, Sweden.|Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, North Carolina 27599-7264, USA.
Patrick F
PF
Sullivan
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston 02114, MA, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki FI-00014, Finland.
Aarno
A
Palotie
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Estonian Genome Center, University of Tartu, Tartu 51010, Estonia.
Tõnu
T
Esko
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 171 77, Sweden.
Christina
C
Hultman
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston 02114, MA, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Benjamin M
BM
Neale
D056915:DNA Copy Number Variations / Q000235:genetics*; D004493:Education; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation / Q000235:genetics*; D065886:Neurodevelopmental Disorders / Q000235:genetics*; D013647:Task Performance and Analysis
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