TY - JOUR

T1 - Rare DNA variants in the brain derived neurotrophic factor gene increase risk for attention deficit hyperactivity disorder

T2 - Molecular Psychiatry

AU - Hawi, Ziarih

AU - Cummins, Tarrant D R

AU - Tong, Janette

AU - Arcos-Burgos, Mauricio

AU - Zhao, Qiongyi

AU - Matthews, Natasha

AU - Newman, Daniel P

AU - Johnson, Beth

AU - Vance, Alasdair

AU - Heussler, Helen S

AU - Levy, Florence

AU - Easteal, Simon

AU - Wray, Naomi

AU - Kenny, Elaine

AU - Morris, Derek

AU - Kent, Lindsey

AU - Gill, Michael

AU - Bellgrove, Mark

N1 - This work was supported by a grant from the National Health and Medical Research Council of Australia (NHMRC) (APP1065677).

PY - 2017/4

Y1 - 2017/4

N2 - Attention deficit hyperactivity disorder (ADHD) is a prevalent and highly heritable disorder of childhood with negative lifetime outcomes. Although candidate gene and genome wide association studies have identified promising common variant signals, these explain only a fraction of the heritability of ADHD. The observation that rare structural variants confer substantial risk to psychiatric disorders suggests that rare variants might explain a portion of the missing heritability for ADHD. Here we performed the first large-scale next generation targeted sequencing study of ADHD in 152 child and adolescent cases and 188 controls across an a priori set of 117 genes. A multi-marker gene level analysis of rare (< 1% frequency) single nucleotide variants (SNVs) revealed that the gene encoding brain derived neurotrophic factor (BDNF) was associated with ADHD at Bonferroni corrected levels. Sanger sequencing confirmed the existence of all novel rare BDNF variants. Our results implicate BDNF as a genetic risk factor for ADHD, potentially by virtue of its critical role in neurodevelopment and synaptic plasticity.

AB - Attention deficit hyperactivity disorder (ADHD) is a prevalent and highly heritable disorder of childhood with negative lifetime outcomes. Although candidate gene and genome wide association studies have identified promising common variant signals, these explain only a fraction of the heritability of ADHD. The observation that rare structural variants confer substantial risk to psychiatric disorders suggests that rare variants might explain a portion of the missing heritability for ADHD. Here we performed the first large-scale next generation targeted sequencing study of ADHD in 152 child and adolescent cases and 188 controls across an a priori set of 117 genes. A multi-marker gene level analysis of rare (< 1% frequency) single nucleotide variants (SNVs) revealed that the gene encoding brain derived neurotrophic factor (BDNF) was associated with ADHD at Bonferroni corrected levels. Sanger sequencing confirmed the existence of all novel rare BDNF variants. Our results implicate BDNF as a genetic risk factor for ADHD, potentially by virtue of its critical role in neurodevelopment and synaptic plasticity.

U2 - 10.1038/mp.2016.117

DO - 10.1038/mp.2016.117

M3 - Article

VL - Advance online

SP - 580

EP - 584

JO - Molecular Psychiatry

JF - Molecular Psychiatry

SN - 1359-4184

ER -