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

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

Author information

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 (rg=-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

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