Identification of Gene Loci That Overlap Between Schizophrenia and Educational Attainment

Stéphanie Le Hellard; Yunpeng Wang; Aree Witoelar; Verena Zuber; Francesco Bettella; Kenneth Hugdahl; Thomas Espeseth; Vidar M Steen; Ingrid Melle; Rahul Desikan; Andrew J Schork; Wesley K Thompson; Anders M Dale; Srdjan Djurovic; Ole A Andreassen; Schizophrenia Working Group of the Psychiatric Genomics Consortium; Stephan Ripke; Benjamin M Neale; Aiden Corvin; Tune H Pers; Esben Agerbo; Ditte Demontis; Thomas Hansen; Mads V Hollegaard; David M. Hougaard; Ole Mors; Anders D Børglum; Thomas Werge; Mark J Daly; Patrick F Sullivan; Michael C O'Donovan

doi:10.1093/schbul/sbw085

Identification of Gene Loci That Overlap Between Schizophrenia and Educational Attainment

Stéphanie Le Hellard, Yunpeng Wang, Aree Witoelar, Verena Zuber, Francesco Bettella, Kenneth Hugdahl, Thomas Espeseth, Vidar M Steen, Ingrid Melle, Rahul Desikan, Andrew J Schork, Wesley K Thompson, Anders M Dale, Srdjan Djurovic, Ole A Andreassen, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Stephan Ripke, Benjamin M Neale, Aiden Corvin, Tune H PersEsben Agerbo, Ditte Demontis, Thomas Hansen, Mads V Hollegaard, David M. Hougaard, Ole Mors, Anders D Børglum, Thomas Werge, Mark J Daly, Patrick F Sullivan, Michael C O'Donovan

Department of Clinical Medicine

30 Citations (Scopus)

Abstract

There is evidence for genetic overlap between cognitive abilities and schizophrenia (SCZ), and genome-wide association studies (GWAS) demonstrate that both SCZ and general cognitive abilities have a strong polygenic component with many single-nucleotide polymorphisms (SNPs) each with a small effect. Here we investigated the shared genetic architecture between SCZ and educational attainment, which is regarded as a "proxy phenotype" for cognitive abilities, but may also reflect other traits. We applied a conditional false discovery rate (condFDR) method to GWAS of SCZ (n = 82 315), college completion ("College," n = 95 427), and years of education ("EduYears," n = 101 069). Variants associated with College or EduYears showed enrichment of association with SCZ, demonstrating polygenic overlap. This was confirmed by an increased replication rate in SCZ. By applying a condFDR threshold <0.01, we identified 18 genomic loci associated with SCZ after conditioning on College and 15 loci associated with SCZ after conditioning on EduYears. Ten of these loci overlapped. Using conjunctional FDR, we identified 10 loci shared between SCZ and College, and 29 loci shared between SCZ and EduYears. The majority of these loci had effects in opposite directions. Our results provide evidence for polygenic overlap between SCZ and educational attainment, and identify novel pleiotropic loci. Other studies have reported genetic overlap between SCZ and cognition, or SCZ and educational attainment, with negative correlation. Importantly, our methods enable identification of bi-directional effects, which highlight the complex relationship between SCZ and educational attainment, and support polygenic mechanisms underlying both cognitive dysfunction and creativity in SCZ.

Original language	English
Journal	Schizophrenia Bulletin
Volume	43
Issue number	3
Pages (from-to)	654-664
ISSN	0586-7614
DOIs	https://doi.org/10.1093/schbul/sbw085
Publication status	Published - 2017

Keywords

Adult
Aptitude
Educational Status
Female
Genetic Loci
Genome-Wide Association Study
Humans
Male
Multifactorial Inheritance
Polymorphism, Single Nucleotide
Schizophrenia/genetics

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Le Hellard, S., Wang, Y., Witoelar, A., Zuber, V., Bettella, F., Hugdahl, K., Espeseth, T., Steen, V. M., Melle, I., Desikan, R., Schork, A. J., Thompson, W. K., Dale, A. M., Djurovic, S., Andreassen, O. A., Schizophrenia Working Group of the Psychiatric Genomics Consortium, Ripke, S., Neale, B. M., Corvin, A., ... O'Donovan, M. C. (2017). Identification of Gene Loci That Overlap Between Schizophrenia and Educational Attainment. Schizophrenia Bulletin, 43(3), 654-664. https://doi.org/10.1093/schbul/sbw085

Le Hellard, S, Wang, Y, Witoelar, A, Zuber, V, Bettella, F, Hugdahl, K, Espeseth, T, Steen, VM, Melle, I, Desikan, R, Schork, AJ, Thompson, WK, Dale, AM, Djurovic, S, Andreassen, OA, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Ripke, S, Neale, BM, Corvin, A, Pers, TH, Agerbo, E, Demontis, D, Hansen, T, Hollegaard, MV, Hougaard, DM, Mors, O, Børglum, AD, Werge, T, Daly, MJ, Sullivan, PF & O'Donovan, MC 2017, 'Identification of Gene Loci That Overlap Between Schizophrenia and Educational Attainment', Schizophrenia Bulletin, vol. 43, no. 3, pp. 654-664. https://doi.org/10.1093/schbul/sbw085

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abstract = "There is evidence for genetic overlap between cognitive abilities and schizophrenia (SCZ), and genome-wide association studies (GWAS) demonstrate that both SCZ and general cognitive abilities have a strong polygenic component with many single-nucleotide polymorphisms (SNPs) each with a small effect. Here we investigated the shared genetic architecture between SCZ and educational attainment, which is regarded as a {"}proxy phenotype{"} for cognitive abilities, but may also reflect other traits. We applied a conditional false discovery rate (condFDR) method to GWAS of SCZ (n = 82 315), college completion ({"}College,{"} n = 95 427), and years of education ({"}EduYears,{"} n = 101 069). Variants associated with College or EduYears showed enrichment of association with SCZ, demonstrating polygenic overlap. This was confirmed by an increased replication rate in SCZ. By applying a condFDR threshold <0.01, we identified 18 genomic loci associated with SCZ after conditioning on College and 15 loci associated with SCZ after conditioning on EduYears. Ten of these loci overlapped. Using conjunctional FDR, we identified 10 loci shared between SCZ and College, and 29 loci shared between SCZ and EduYears. The majority of these loci had effects in opposite directions. Our results provide evidence for polygenic overlap between SCZ and educational attainment, and identify novel pleiotropic loci. Other studies have reported genetic overlap between SCZ and cognition, or SCZ and educational attainment, with negative correlation. Importantly, our methods enable identification of bi-directional effects, which highlight the complex relationship between SCZ and educational attainment, and support polygenic mechanisms underlying both cognitive dysfunction and creativity in SCZ.",

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note = "{\textcopyright} The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: [email protected].",

year = "2017",

doi = "10.1093/schbul/sbw085",

language = "English",

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pages = "654--664",

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T1 - Identification of Gene Loci That Overlap Between Schizophrenia and Educational Attainment

AU - Le Hellard, Stéphanie

AU - Wang, Yunpeng

AU - Witoelar, Aree

AU - Zuber, Verena

AU - Bettella, Francesco

AU - Hugdahl, Kenneth

AU - Espeseth, Thomas

AU - Steen, Vidar M

AU - Melle, Ingrid

AU - Desikan, Rahul

AU - Schork, Andrew J

AU - Thompson, Wesley K

AU - Dale, Anders M

AU - Djurovic, Srdjan

AU - Andreassen, Ole A

AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium

AU - Ripke, Stephan

AU - Neale, Benjamin M

AU - Corvin, Aiden

AU - Pers, Tune H

AU - Agerbo, Esben

AU - Demontis, Ditte

AU - Hansen, Thomas

AU - Hollegaard, Mads V

AU - Hougaard, David M.

AU - Mors, Ole

AU - Børglum, Anders D

AU - Werge, Thomas

AU - Daly, Mark J

AU - Sullivan, Patrick F

AU - O'Donovan, Michael C

PY - 2017

Y1 - 2017

N2 - There is evidence for genetic overlap between cognitive abilities and schizophrenia (SCZ), and genome-wide association studies (GWAS) demonstrate that both SCZ and general cognitive abilities have a strong polygenic component with many single-nucleotide polymorphisms (SNPs) each with a small effect. Here we investigated the shared genetic architecture between SCZ and educational attainment, which is regarded as a "proxy phenotype" for cognitive abilities, but may also reflect other traits. We applied a conditional false discovery rate (condFDR) method to GWAS of SCZ (n = 82 315), college completion ("College," n = 95 427), and years of education ("EduYears," n = 101 069). Variants associated with College or EduYears showed enrichment of association with SCZ, demonstrating polygenic overlap. This was confirmed by an increased replication rate in SCZ. By applying a condFDR threshold <0.01, we identified 18 genomic loci associated with SCZ after conditioning on College and 15 loci associated with SCZ after conditioning on EduYears. Ten of these loci overlapped. Using conjunctional FDR, we identified 10 loci shared between SCZ and College, and 29 loci shared between SCZ and EduYears. The majority of these loci had effects in opposite directions. Our results provide evidence for polygenic overlap between SCZ and educational attainment, and identify novel pleiotropic loci. Other studies have reported genetic overlap between SCZ and cognition, or SCZ and educational attainment, with negative correlation. Importantly, our methods enable identification of bi-directional effects, which highlight the complex relationship between SCZ and educational attainment, and support polygenic mechanisms underlying both cognitive dysfunction and creativity in SCZ.

AB - There is evidence for genetic overlap between cognitive abilities and schizophrenia (SCZ), and genome-wide association studies (GWAS) demonstrate that both SCZ and general cognitive abilities have a strong polygenic component with many single-nucleotide polymorphisms (SNPs) each with a small effect. Here we investigated the shared genetic architecture between SCZ and educational attainment, which is regarded as a "proxy phenotype" for cognitive abilities, but may also reflect other traits. We applied a conditional false discovery rate (condFDR) method to GWAS of SCZ (n = 82 315), college completion ("College," n = 95 427), and years of education ("EduYears," n = 101 069). Variants associated with College or EduYears showed enrichment of association with SCZ, demonstrating polygenic overlap. This was confirmed by an increased replication rate in SCZ. By applying a condFDR threshold <0.01, we identified 18 genomic loci associated with SCZ after conditioning on College and 15 loci associated with SCZ after conditioning on EduYears. Ten of these loci overlapped. Using conjunctional FDR, we identified 10 loci shared between SCZ and College, and 29 loci shared between SCZ and EduYears. The majority of these loci had effects in opposite directions. Our results provide evidence for polygenic overlap between SCZ and educational attainment, and identify novel pleiotropic loci. Other studies have reported genetic overlap between SCZ and cognition, or SCZ and educational attainment, with negative correlation. Importantly, our methods enable identification of bi-directional effects, which highlight the complex relationship between SCZ and educational attainment, and support polygenic mechanisms underlying both cognitive dysfunction and creativity in SCZ.

KW - Adult

KW - Aptitude

KW - Educational Status

KW - Female

KW - Genetic Loci

KW - Genome-Wide Association Study

KW - Humans

KW - Male

KW - Multifactorial Inheritance

KW - Polymorphism, Single Nucleotide

KW - Schizophrenia/genetics

U2 - 10.1093/schbul/sbw085

DO - 10.1093/schbul/sbw085

M3 - Journal article

C2 - 27338279

SN - 0586-7614

VL - 43

SP - 654

EP - 664

JO - Schizophrenia Bulletin

JF - Schizophrenia Bulletin

IS - 3

ER -

Identification of Gene Loci That Overlap Between Schizophrenia and Educational Attainment

Abstract

Keywords

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