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      Interplay between genome-wide implicated genetic variants and environmental factors related to childhood antisocial behavior in the UK ALSPAC cohort

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          Abstract

          We investigated gene–environment (G × E) interactions related to childhood antisocial behavior between polymorphisms implicated by recent genome-wide association studies (GWASs) and two key environmental adversities (maltreatment and smoking during pregnancy) in a large population cohort (ALSPAC). We also studied the MAOA candidate gene and addressed comorbid attention-deficit/hyperactivity disorder (ADHD). ALSPAC is a large, prospective, ethnically homogeneous British cohort. Our outcome consisted of mother-rated conduct disorder symptom scores at age 7;9 years. G × E interactions were tested in a sex-stratified way ( α = 0.0031) for four GWAS-implicated variants (for males, rs4714329 and rs9471290; for females, rs2764450 and rs11215217), and a length polymorphism near the MAOA-promoter region. We found that males with rs4714329-GG ( P = 0.0015) and rs9471290-AA ( P = 0.0001) genotypes were significantly more susceptible to effects of smoking during pregnancy in relation to childhood antisocial behavior. Females with the rs11215217-TC genotype ( P = 0.0018) were significantly less susceptible to effects of maltreatment, whereas females with the MAOA-HL genotype ( P = 0.0002) were more susceptible to maltreatment effects related to antisocial behavior. After adjustment for comorbid ADHD symptomatology, aforementioned G × E’s remained significant, except for rs11215217 × maltreatment, which retained only nominal significance. Genetic variants implicated by recent GWASs of antisocial behavior moderated associations of smoking during pregnancy and maltreatment with childhood antisocial behavior in the general population. While we also found a G × E interaction between the candidate gene MAOA and maltreatment, we were mostly unable to replicate the previous results regarding MAOA–G × E’s. Future studies should, in addition to genome-wide implicated variants, consider polygenic and/or multimarker analyses and take into account potential sex stratification.

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          The online version of this article (10.1007/s00406-018-0964-5) contains supplementary material, which is available to authorized users.

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          Most cited references47

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          Rare and common variants: twenty arguments.

          Genome-wide association studies have greatly improved our understanding of the genetic basis of disease risk. The fact that they tend not to identify more than a fraction of the specific causal loci has led to divergence of opinion over whether most of the variance is hidden as numerous rare variants of large effect or as common variants of very small effect. Here I review 20 arguments for and against each of these models of the genetic basis of complex traits and conclude that both classes of effect can be readily reconciled.
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            ALSPAC--the Avon Longitudinal Study of Parents and Children. I. Study methodology.

            ALSPAC (The Avon Longitudinal Study of Parents and Children, formerly the Avon Longitudinal Study of Pregnancy and Childhood) was specifically designed to determine ways in which the individual's genotype combines with environmental pressures to influence health and development. To date, there are comprehensive data on approximately 10,000 children and their parents, from early pregnancy until the children are aged between 8 and 9. The study aims to continue to collect detailed data on the children as they go through puberty noting, in particular, changes in anthropometry, attitudes and behaviour, fitness and other cardiovascular risk factors, bone mineralisation, allergic symptoms and mental health. The study started early during pregnancy and collected very detailed data from the mother and her partner before the child was born. This not only provided accurate data on concurrent features, especially medication, symptoms, diet and lifestyle, attitudes and behaviour, social and environmental features, but was unbiased by parental knowledge of any problems that the child might develop. From the time of the child's birth many different aspects of the child's environment have been monitored and a wide range of phenotypic data collected. By virtue of being based in one geographic area, linkage to medical and educational records is relatively simple, and hands-on assessments of children and parents using local facilities has the advantage of high quality control. The comprehensiveness of the ALSPAC approach with a total population sample unselected by disease status, and the availability of parental genotypes, provides an adequate sample for statistical analysis and for avoiding spurious results. The study has an open policy in regard to collaboration within strict confidentiality rules.
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              A functional polymorphism in the monoamine oxidase A gene promoter.

              We describe a new polymorphism upstream of the gene for monoamine oxidase A (MAOA), an important enzyme in human physiology and behavior. The polymorphism, which is located 1.2 kb upstream of the MAOA coding sequences, consists of a 30-bp repeated sequence present in 3, 3.5, 4, or 5 copies. The polymorphism is in linkage disequilibrium with other MAOA and MAOB gene markers and displays significant variations in allele frequencies across ethnic groups. The polymorphism has been shown to affect the transcriptional activity of the MAOA gene promoter by gene fusion and transfection experiments involving three different cell types. Alleles with 3.5 or 4 copies of the repeat sequence are transcribed 2-10 times more efficiently than those with 3 or 5 copies of the repeat, suggesting an optimal length for the regulatory region. This promoter region polymorphism may be useful as both a functional and an anonymous genetic marker for MAOA.
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                Author and article information

                Contributors
                +31 50 361 61 61 , i.h.ruisch@umcg.nl
                a.dietrich@accare.nl
                j.glennon@donders.ru.nl
                jan.buitelaar@radboudumc.nl
                p.hoekstra@accare.nl
                Journal
                Eur Arch Psychiatry Clin Neurosci
                Eur Arch Psychiatry Clin Neurosci
                European Archives of Psychiatry and Clinical Neuroscience
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0940-1334
                1433-8491
                19 December 2018
                19 December 2018
                2019
                : 269
                : 6
                : 741-752
                Affiliations
                [1 ]ISNI 0000 0000 9558 4598, GRID grid.4494.d, Department of Child and Adolescent Psychiatry, University of Groningen, , University Medical Center Groningen, ; Hanzeplein 1, 9713GZ Groningen, The Netherlands
                [2 ]ISNI 0000 0004 0444 9382, GRID grid.10417.33, Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, , Radboud University Medical Center, ; Geert Grooteplein Zuid 10, 6525GA Nijmegen, The Netherlands
                [3 ]ISNI 0000 0004 0624 8031, GRID grid.461871.d, Karakter Child and Adolescent Psychiatry University Centre, ; Reinier Postlaan 12, 6525GC Nijmegen, The Netherlands
                Article
                964
                10.1007/s00406-018-0964-5
                6689282
                30569215
                a0aa9895-eef1-45a7-b9c9-1034248c1147
                © The Author(s) 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 9 July 2018
                : 6 December 2018
                Funding
                Funded by: European Community’s Seventh Framework Programme
                Award ID: 603016
                Categories
                Original Paper
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2019

                Neurosciences
                alspac,antisocial behavior,aggression,gene–environment interaction,maltreatment,smoking during pregnancy

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