Novel Loci Associated With Attention-Deficit/Hyperactivity Disorder Are Revealed by Leveraging Polygenic Overlap With Educational Attainment

Alexey A Shadrin; Olav B Smeland; Tetyana Zayats; Andrew J Schork; Oleksandr Frei; Francesco Bettella; Aree Witoelar; Wen Li; Jon A Eriksen; Florian Krull; Srdjan Djurovic; Stephen V Faraone; Ted Reichborn-Kjennerud; Wesley K Thompson; Stefan Johansson; Jan Haavik; Anders M Dale; Yunpeng Wang; Ole A Andreassen

doi:10.1016/j.jaac.2017.11.013

Novel Loci Associated With Attention-Deficit/Hyperactivity Disorder Are Revealed by Leveraging Polygenic Overlap With Educational Attainment

J Am Acad Child Adolesc Psychiatry. 2018 Feb;57(2):86-95. doi: 10.1016/j.jaac.2017.11.013. Epub 2017 Nov 26.

Authors

Alexey A Shadrin¹, Olav B Smeland², Tetyana Zayats³, Andrew J Schork⁴, Oleksandr Frei², Francesco Bettella², Aree Witoelar², Wen Li², Jon A Eriksen², Florian Krull², Srdjan Djurovic⁵, Stephen V Faraone⁶, Ted Reichborn-Kjennerud⁷, Wesley K Thompson⁸, Stefan Johansson⁹, Jan Haavik¹⁰, Anders M Dale¹¹, Yunpeng Wang¹², Ole A Andreassen²

Affiliations

¹ NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. Electronic address: a.a.shadrin@medisin.uio.no.
² NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
³ K.G. Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, Bergen, Norway.
⁴ University of California, San Diego and Institute of Biological Psychiatry, Medical Health Center, Sct. Hans Hospital and University of Copenhagen, Copenhagen, Denmark.
⁵ Oslo University Hospital, Oslo, and NORMENT, KG Jebsen Centre for Psychosis Research, University of Bergen.
⁶ KG Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, SUNY Upstate Medical University, Syracuse, New York.
⁷ Division of Mental Health, Norwegian Institute of Public Health, Oslo, and Institute of Clinical Medicine, University of Oslo.
⁸ University of California, San Diego.
⁹ K.G. Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, Bergen, Norway; Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
¹⁰ K.G. Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, Bergen, Norway; Division of Psychiatry, Haukeland University Hospital.
¹¹ NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, and University of California, San Diego.
¹² NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; University of California, San Diego, La Jolla, CA.

Abstract

Objective: Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable psychiatric condition. By exploiting the reported relationship between ADHD and educational attainment (EA), we aimed to improve discovery of ADHD-associated genetic variants and to investigate genetic overlap between these phenotypes.

Method: A conditional/conjunctional false discovery rate (condFDR/conjFDR) method was applied to genome-wide association study (GWAS) data on ADHD (2,064 trios, 896 cases, and 2,455 controls) and EA (n=328,917) to identify ADHD-associated loci and loci overlapping between ADHD and EA. Identified single nucleotide polymorphisms (SNPs) were tested for association in an independent population-based study of ADHD symptoms (n=17,666). Genetic correlation between ADHD and EA was estimated using LD score regression and Pearson correlation.

Results: At levels of condFDR<0.01 and conjFDR<0.05, we identified 5 ADHD-associated loci, 3 of these being shared between ADHD and EA. None of these loci had been identified in the primary ADHD GWAS, demonstrating the increased power provided by the condFDR/conjFDR analysis. Leading SNPs for 4 of 5 identified regions are in introns of protein coding genes (KDM4A, MEF2C, PINK1, RUNX1T1), whereas the remaining one is an intergenic SNP on chromosome 2 at 2p24. Consistent direction of effects in the independent study of ADHD symptoms was shown for 4 of 5 identified loci. A polygenic overlap between ADHD and EA was supported by significant genetic correlation (r_g=-0.403, p=7.90×10^-8) and >10-fold mutual enrichment of SNPs associated with both traits.

Conclusion: We identified 5 novel loci associated with ADHD and provided evidence for a shared genetic basis between ADHD and EA. These findings could aid understanding of the genetic risk architecture of ADHD and its relation to EA.

Keywords: attention-deficit/hyperactivity disorder; conditional/conjunctional false discovery rate; educational attainment; genetic overlap.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Attention Deficit Disorder with Hyperactivity / diagnosis*
Attention Deficit Disorder with Hyperactivity / genetics
Child
Educational Status
Female
Genetic Predisposition to Disease*
Genome-Wide Association Study / methods*
Humans
Jumonji Domain-Containing Histone Demethylases / genetics
Male
Multifactorial Inheritance / genetics*
Phenotype
Polymorphism, Single Nucleotide

Substances

Jumonji Domain-Containing Histone Demethylases
KDM4A protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding