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      On the importance of parenting in externalizing disorders: an evaluation of indirect genetic effects in families

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          Abstract

          Background

          Theoretical models of the development of childhood externalizing disorders emphasize the role of parents. Empirical studies have not been able to identify specific aspects of parental behaviors explaining a considerable proportion of the observed individual differences in externalizing problems. The problem is complicated by the contribution of genetic factors to externalizing problems, as parents provide both genes and environments to their children. We studied the joint contributions of direct genetic effects of children and the indirect genetic effects of parents through the environment on externalizing problems.

          Methods

          The study used genome‐wide single nucleotide polymorphism data from 9,675 parent–offspring trios participating in the Norwegian Mother Father and child cohort study. Based on genomic relatedness matrices, we estimated the contribution of direct genetic effects and indirect maternal and paternal genetic effects on ADHD, conduct and disruptive behaviors at 8 years of age.

          Results

          Models including indirect parental genetic effects were preferred for the ADHD symptoms of inattention and hyperactivity, and conduct problems, but not oppositional defiant behaviors. Direct genetic effects accounted for 11% to 24% of the variance, whereas indirect parental genetic effects accounted for 0% to 16% in ADHD symptoms and conduct problems. The correlation between direct and indirect genetic effects, or gene–environment correlations, decreased the variance with 16% and 13% for conduct and inattention problems, and increased the variance with 6% for hyperactivity problems.

          Conclusions

          This study provides empirical support to the notion that parents have a significant role in the development of childhood externalizing behaviors. The parental contribution to decrease in variation of inattention and conduct problems by gene–environment correlations would limit the number of children reaching clinical ranges in symptoms. Not accounting for indirect parental genetic effects can lead to both positive and negative bias when identifying genetic variants for childhood externalizing behaviors.

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          Most cited references47

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          Second-generation PLINK: rising to the challenge of larger and richer datasets

          PLINK 1 is a widely used open-source C/C++ toolset for genome-wide association studies (GWAS) and research in population genetics. However, the steady accumulation of data from imputation and whole-genome sequencing studies has exposed a strong need for even faster and more scalable implementations of key functions. In addition, GWAS and population-genetic data now frequently contain probabilistic calls, phase information, and/or multiallelic variants, none of which can be represented by PLINK 1's primary data format. To address these issues, we are developing a second-generation codebase for PLINK. The first major release from this codebase, PLINK 1.9, introduces extensive use of bit-level parallelism, O(sqrt(n))-time/constant-space Hardy-Weinberg equilibrium and Fisher's exact tests, and many other algorithmic improvements. In combination, these changes accelerate most operations by 1-4 orders of magnitude, and allow the program to handle datasets too large to fit in RAM. This will be followed by PLINK 2.0, which will introduce (a) a new data format capable of efficiently representing probabilities, phase, and multiallelic variants, and (b) extensions of many functions to account for the new types of information. The second-generation versions of PLINK will offer dramatic improvements in performance and compatibility. For the first time, users without access to high-end computing resources can perform several essential analyses of the feature-rich and very large genetic datasets coming into use.
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            GCTA: a tool for genome-wide complex trait analysis.

            For most human complex diseases and traits, SNPs identified by genome-wide association studies (GWAS) explain only a small fraction of the heritability. Here we report a user-friendly software tool called genome-wide complex trait analysis (GCTA), which was developed based on a method we recently developed to address the "missing heritability" problem. GCTA estimates the variance explained by all the SNPs on a chromosome or on the whole genome for a complex trait rather than testing the association of any particular SNP to the trait. We introduce GCTA's five main functions: data management, estimation of the genetic relationships from SNPs, mixed linear model analysis of variance explained by the SNPs, estimation of the linkage disequilibrium structure, and GWAS simulation. We focus on the function of estimating the variance explained by all the SNPs on the X chromosome and testing the hypotheses of dosage compensation. The GCTA software is a versatile tool to estimate and partition complex trait variation with large GWAS data sets.
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              An Atlas of Genetic Correlations across Human Diseases and Traits

              Identifying genetic correlations between complex traits and diseases can provide useful etiological insights and help prioritize likely causal relationships. The major challenges preventing estimation of genetic correlation from genome-wide association study (GWAS) data with current methods are the lack of availability of individual genotype data and widespread sample overlap among meta-analyses. We circumvent these difficulties by introducing a technique – cross-trait LD Score regression – for estimating genetic correlation that requires only GWAS summary statistics and is not biased by sample overlap. We use this method to estimate 276 genetic correlations among 24 traits. The results include genetic correlations between anorexia nervosa and schizophrenia, anorexia and obesity and associations between educational attainment and several diseases. These results highlight the power of genome-wide analyses, since there currently are no significantly associated SNPs for anorexia nervosa and only three for educational attainment.
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                Author and article information

                Contributors
                e.m.eilertsen@psykologi.uio.no
                Journal
                J Child Psychol Psychiatry
                J Child Psychol Psychiatry
                10.1111/(ISSN)1469-7610
                JCPP
                Journal of Child Psychology and Psychiatry, and Allied Disciplines
                John Wiley and Sons Inc. (Hoboken )
                0021-9630
                1469-7610
                02 July 2022
                October 2022
                : 63
                : 10 , New horizons in gene‐environment interplay in developmental psychopathology ( doiID: 10.1111/jcpp.v63.10 )
                : 1186-1195
                Affiliations
                [ 1 ] Department of Psychology, PROMENTA Research Center University of Oslo Oslo Norway
                [ 2 ] Centre for Fertility and Health Norwegian Institute of Public Health Oslo Norway
                [ 3 ] Division of Psychology and Language Sciences University College London London UK
                [ 4 ] MRC Social, Genetic and Developmental Psychiatry Centre Institute of Psychiatry, King's College London UK
                [ 5 ] Department of Clinical Science, Center for Diabetes Research University of Bergen Bergen Norway
                [ 6 ] Children and Youth Clinic Haukeland University Hospital Bergen Norway
                [ 7 ] Division of Mental Health and Addiction, NORMENT Oslo University Hospital Oslo Norway
                [ 8 ] Institute of Clinical Medicine University of Oslo Oslo Norway
                [ 9 ] Department of Mental Disorders Norwegian Institute of Public Health Oslo Norway
                [ 10 ] Nic Waals Institute, Lovisenberg Diaconal Hospital Oslo Norway
                [ 11 ] Social, Genetic and Developmental Psychiatry Centre Institute of Psychiatry, Psychology and Neuroscience, King's College London London UK
                [ 12 ] School of Pharmacy University of Oslo Oslo Norway
                Author notes
                [*] [* ] Correspondence

                Espen M. Eilertsen, Harald Schjelderups hus, Forskningsveien 3A, 0373 Oslo, Norway; Email: e.m.eilertsen@ 123456psykologi.uio.no

                Author information
                https://orcid.org/0000-0003-3444-4251
                https://orcid.org/0000-0001-5133-7170
                https://orcid.org/0000-0002-9268-0423
                https://orcid.org/0000-0002-6825-3499
                Article
                JCPP13654 JCPP-OA-2021-00724.R1
                10.1111/jcpp.13654
                9796091
                35778910
                2c6263f1-574e-4041-a156-9bd5949e4506
                © 2022 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 08 May 2022
                Page count
                Figures: 2, Tables: 2, Pages: 1195, Words: 8757
                Funding
                Funded by: H2020 European Research Council , doi 10.13039/100010663;
                Award ID: 818425
                Award ID: 863981
                Funded by: H2020 Marie Skłodowska‐Curie Actions , doi 10.13039/100010665;
                Award ID: 894675
                Funded by: Norges Forskningsråd , doi 10.13039/501100005416;
                Award ID: 223273
                Award ID: 229624
                Award ID: 262177
                Award ID: 262700
                Award ID: 273659
                Award ID: 288083
                Award ID: 300668
                Funded by: Utdannings‐ og forskningsdepartementet , doi 10.13039/501100008724;
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                October 2022
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.2.3 mode:remove_FC converted:28.12.2022

                Clinical Psychology & Psychiatry
                externalizing disorders,parenting,indirect genetic effects,gene–environment correlation,moba

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