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. 2016 Jul;171(5):733-47.
doi: 10.1002/ajmg.b.32434. Epub 2016 Mar 29.

Genome-wide analyses of aggressiveness in attention-deficit hyperactivity disorder

Erlend J Brevik  1   2   3 , Marjolein M J van Donkelaar  4 , Heike Weber  5 , Cristina Sánchez-Mora  6   7   8 , Christian Jacob  9 , Olga Rivero  10 , Sarah Kittel-Schneider  10 , Iris Garcia-Martínez  6   7 , Marcel Aebi  11   12 , Kimm van Hulzen  4 , Bru Cormand  13   14   15 , Josep A Ramos-Quiroga  6   7   8   16 ; IMAGE Consortium; Klaus-Peter Lesch  9   17 , Andreas Reif  5 , Marta Ribasés  6   7   8 , Barbara Franke  4   18 , Maj-Britt Posserud  1   2 , Stefan Johansson  19   20 , Astri J Lundervold  2   3 , Jan Haavik  1   2 , Tetyana Zayats  2
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Genome-wide analyses of aggressiveness in attention-deficit hyperactivity disorder

Erlend J Brevik et al. Am J Med Genet B Neuropsychiatr Genet. 2016 Jul.

Abstract

Aggressiveness is a behavioral trait that has the potential to be harmful to individuals and society. With an estimated heritability of about 40%, genetics is important in its development. We performed an exploratory genome-wide association (GWA) analysis of childhood aggressiveness in attention deficit hyperactivity disorder (ADHD) to gain insight into the underlying biological processes associated with this trait. Our primary sample consisted of 1,060 adult ADHD patients (aADHD). To further explore the genetic architecture of childhood aggressiveness, we performed enrichment analyses of suggestive genome-wide associations observed in aADHD among GWA signals of dimensions of oppositionality (defiant/vindictive and irritable dimensions) in childhood ADHD (cADHD). No single polymorphism reached genome-wide significance (P < 5.00E-08). The strongest signal in aADHD was observed at rs10826548, within a long noncoding RNA gene (beta = -1.66, standard error (SE) = 0.34, P = 1.07E-06), closely followed by rs35974940 in the neurotrimin gene (beta = 3.23, SE = 0.67, P = 1.26E-06). The top GWA SNPs observed in aADHD showed significant enrichment of signals from both the defiant/vindictive dimension (Fisher's P-value = 2.28E-06) and the irritable dimension in cADHD (Fisher's P-value = 0.0061). In sum, our results identify a number of biologically interesting markers possibly underlying childhood aggressiveness and provide targets for further genetic exploration of aggressiveness across psychiatric disorders. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

Keywords: ADHD; GWAS; aggression.

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Figures

Figure 1
Figure 1
Plot of the locus surrounding rs10826548. SNPs are plotted by position on chromosome 10 against GWA P‐values for aggressive behavior measure in aADHD. Estimated recombination rates from HapMap are plotted in bright red to reflect local LD structure. The SNPs surrounding rs10826548 are color‐coded to reflect their LD with it (according to pair‐wise r2 values from the HapMap CEU database). SNPs with LD r2 ≥ 0.2 are plotted at the bottom of the graph with LD color‐coding specified in the top right corner. “Genes” refers to protein‐coding genes in the presented region. “lincRNAsAllCellTypeTopView” reflects the data from lncRNA USCS track in brain tissue. “tfbsConsSites” reflects the TFBS UCSC track.
Figure 2
Figure 2
Plot of the locus surrounding rs35974940. SNPs are plotted by position on chromosome 11 against GWA P‐values for aggressive behavior measure in aADHD. Estimated recombination rates from HapMap are plotted in bright red to reflect local LD structure. The SNPs surrounding rs35974940 are color‐coded to reflect their LD with it (according to pair‐wise r2 values from the HapMap CEU database). SNPs with LD r2 ≥ 0.2 are plotted at the bottom of the graph with LD color‐coding specified in the top right corner. “Genes” refers to protein‐coding genes in the presented region. “lincRNAsAllCellTypeTopView” reflects the data from lncRNA USCS track in brain tissue. “tfbsConsSites” reflects the TFBS UCSC track.
Figure 3
Figure 3
Enrichment and direction of effect among GWA signals of oppositional dimensions in cADHD and WURS‐derived childhood aggressiveness in aADHD. Part A reflects the proportion of SNPs nominally associated (P < 0.05) with each examined oppositional dimension in cADHD (defiant/vindictive and irritable) among suggestive signals (P ≤ 1.00E‐03) of association with childhood aggressiveness in aADHD. Reported P‐values are those of Fisher's exact test. Parts B and C reflect directions of effect of 24 independent nominally significant loci in GWA analyses of defiant/vindictive dimension in cADHD and childhood aggressiveness in aADHD (part B) as well as 17 independent nominally significant loci in GWA analyses of irritable dimension in cADHD and childhood aggressiveness in aADHD (part C). Linear regression r2 measures and P‐values are shown.
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