Publications by authors named "Abdel Abdellaoui"

82 Publications

Genomic evidence consistent with antagonistic pleiotropy may help explain the evolutionary maintenance of same-sex sexual behaviour in humans.

Nat Hum Behav 2021 Sep 23;5(9):1251-1258. Epub 2021 Aug 23.

Department of Psychiatry, Amsterdam UMC location AMC, University of Amsterdam, Amsterdam, the Netherlands.

Human same-sex sexual behaviour (SSB) is heritable, confers no immediately obvious direct reproductive or survival benefit and can divert mating effort from reproductive opportunities. This presents a Darwinian paradox: why has SSB been maintained despite apparent selection against it? We show that genetic effects associated with SSB may, in individuals who only engage in opposite-sex sexual behaviour (OSB individuals), confer a mating advantage. Using results from a recent genome-wide association study of SSB and a new genome-wide association study on number of opposite-sex sexual partners in 358,426 individuals, we show that, among OSB individuals, genetic effects associated with SSB are associated with having more opposite-sex sexual partners. Computer simulations suggest that such a mating advantage for alleles associated with SSB could help explain how it has been evolutionarily maintained. Caveats include the cultural specificity of our UK and US samples, the societal regulation of sexual behaviour in these populations, the difficulty of measuring mating success and the fact that measured variants capture a minority of the total genetic variation in the traits.
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http://dx.doi.org/10.1038/s41562-021-01168-8DOI Listing
September 2021

Dissecting polygenic signals from genome-wide association studies on human behaviour.

Nat Hum Behav 2021 06 13;5(6):686-694. Epub 2021 May 13.

Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Genome-wide association studies on human behavioural traits are producing large amounts of polygenic signals with significant predictive power and potentially useful biological clues. Behavioural traits are more distal and are less directly under biological control compared with physical characteristics, which makes the associated genetic effects harder to interpret. The results of genome-wide association studies for human behaviour are likely made up of a composite of signals from different sources. While sample sizes continue to increase, we outline additional steps that need to be taken to better delineate the origin of the increasingly stronger polygenic signals. In addition to genetic effects on the traits themselves, the major sources of polygenic signals are those that are associated with correlated traits, environmental effects and ascertainment bias. Advances in statistical approaches that disentangle polygenic effects from different traits as well as extending data collection to families and social circles with better geographical coverage will probably contribute to filling the gap of knowledge between genetic effects and behavioural outcomes.
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http://dx.doi.org/10.1038/s41562-021-01110-yDOI Listing
June 2021

Genetic analyses identify widespread sex-differential participation bias.

Nat Genet 2021 05 22;53(5):663-671. Epub 2021 Apr 22.

Faculty of Behavioural and Movement Sciences, Biological Psychology, Vrije Universiteit, Amsterdam, the Netherlands.

Genetic association results are often interpreted with the assumption that study participation does not affect downstream analyses. Understanding the genetic basis of participation bias is challenging since it requires the genotypes of unseen individuals. Here we demonstrate that it is possible to estimate comparative biases by performing a genome-wide association study contrasting one subgroup versus another. For example, we showed that sex exhibits artifactual autosomal heritability in the presence of sex-differential participation bias. By performing a genome-wide association study of sex in approximately 3.3 million males and females, we identified over 158 autosomal loci spuriously associated with sex and highlighted complex traits underpinning differences in study participation between the sexes. For example, the body mass index-increasing allele at FTO was observed at higher frequency in males compared to females (odds ratio = 1.02, P = 4.4 × 10). Finally, we demonstrated how these biases can potentially lead to incorrect inferences in downstream analyses and propose a conceptual framework for addressing such biases. Our findings highlight a new challenge that genetic studies may face as sample sizes continue to grow.
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http://dx.doi.org/10.1038/s41588-021-00846-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611642PMC
May 2021

Response to Comment on "Large-scale GWAS reveals insights into the genetic architecture of same-sex sexual behavior".

Science 2021 03;371(6536)

Centre for Psychology and Evolution, School of Psychology, University of Queensland, St. Lucia, Brisbane, QLD 4072, Australia.

Hamer argue that the variable "ever versus never had a same-sex partner" does not capture the complexity of human sexuality. We agree and said so in our paper. But Hamer neglect to mention that we also reported follow-up analyses showing substantial overlap of the genetic influences on our main variable and on more nuanced measures of sexual behavior, attraction, and identity.
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http://dx.doi.org/10.1126/science.aba5693DOI Listing
March 2021

1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans.

Transl Psychiatry 2021 03 22;11(1):182. Epub 2021 Mar 22.

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
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http://dx.doi.org/10.1038/s41398-021-01213-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985307PMC
March 2021

Genetic correlates of socio-economic status influence the pattern of shared heritability across mental health traits.

Nat Hum Behav 2021 08 8;5(8):1065-1073. Epub 2021 Mar 8.

QIMR Berghofer, Translational Neurogenomics Group, Brisbane, Queensland, Australia.

Epidemiological studies show high comorbidity between different mental health problems, indicating that individuals with a diagnosis of one disorder are more likely to develop other mental health problems. Genetic studies reveal substantial sharing of genetic factors across mental health traits. However, mental health is also genetically correlated with socio-economic status (SES), and it is therefore important to investigate and disentangle the genetic relationship between mental health and SES. We used summary statistics from large genome-wide association studies (average N ~ 160,000) to estimate the genetic overlap across nine psychiatric disorders and seven substance use traits and explored the genetic influence of three different indicators of SES. Using genomic structural equation modelling, we show significant changes in patterns of genetic correlations after partialling out SES-associated genetic variation. Our approach allows the separation of disease-specific genetic variation and genetic variation shared with SES, thereby improving our understanding of the genetic architecture of mental health.
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http://dx.doi.org/10.1038/s41562-021-01053-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376746PMC
August 2021

Phenotypic covariance across the entire spectrum of relatedness for 86 billion pairs of individuals.

Nat Commun 2021 02 16;12(1):1050. Epub 2021 Feb 16.

Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.

Attributing the similarity between individuals to genetic and non-genetic factors is central to genetic analyses. In this paper we use the genomic relationship ([Formula: see text]) among 417,060 individuals to investigate the phenotypic covariance between pairs of individuals for 32 traits across the spectrum of relatedness, from unrelated pairs through to identical twins. We find linear relationships between phenotypic covariance and [Formula: see text] that agree with the SNP-based heritability ([Formula: see text]) in unrelated pairs ([Formula: see text]), and with pedigree-estimated heritability in close relatives ([Formula: see text]). The covariance increases faster than [Formula: see text] in distant relatives ([Formula: see text]), and we attribute this to imperfect linkage disequilibrium between causal variants and the common variants used to construct [Formula: see text]. We also examine the effect of assortative mating on heritability estimates from different experimental designs. We find that full-sib identity-by-descent regression estimates for height (0.66 s.e. 0.07) are consistent with estimates from close relatives (0.82 s.e. 0.04) after accounting for the effect of assortative mating.
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http://dx.doi.org/10.1038/s41467-021-21283-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886899PMC
February 2021

Genomic relationships across psychiatric disorders including substance use disorders.

Drug Alcohol Depend 2021 03 19;220:108535. Epub 2021 Jan 19.

Department of Psychiatry, Amsterdam UMC, University of Amsterdam, 1105 AZ, Amsterdam, the Netherlands. Electronic address:

Background: A recent study investigated the genetic associations and latent genetic structure among eight psychiatric disorders using findings from genome-wide association studies (GWASs). No data from substance use disorders were included, while these represent an important category of mental disorders and could influence the latent genetic structure. We extended the original paper by recreating the genetic relationship matrix, graph, and latent genetic factor structure, including additional data from substance use disorders.

Methods: We used GWAS summary statistics of 11 psychiatric disorders, including alcohol dependence, nicotine dependence, and cannabis use disorder. We estimated genetic correlations between all traits in Linkage Disequilibrium-Score Regression. A graph was created to illustrate the network of genetic correlations. We then used the genetic relationships to model a latent genetic factor structure.

Results: Alcohol and nicotine dependence showed significant genetic correlations with several other psychiatric disorders, including ADHD, schizophrenia, and major depression. Cannabis use disorder was only significantly associated with ADHD. The addition of substance use disorders resulted in some changes in the latent structure of the factor model when compared to the original model including eight disorders. All substance use disorders contributed mostly to Factor 3, a heterogeneous factor with also loadings from ADHD, major depression, Autism Spectrum Disorders, and Tourette Syndrome.

Conclusions: Alcohol and nicotine dependence show widespread genetic correlations with other psychiatric disorders. Including substance use disorders in the factor analysis results in some changes in the underlying genetic factor structure. Given the instability of such models, identified structures should be interpreted with caution.
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http://dx.doi.org/10.1016/j.drugalcdep.2021.108535DOI Listing
March 2021

Investigating the genetic architecture of noncognitive skills using GWAS-by-subtraction.

Nat Genet 2021 01 7;53(1):35-44. Epub 2021 Jan 7.

Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.

Little is known about the genetic architecture of traits affecting educational attainment other than cognitive ability. We used genomic structural equation modeling and prior genome-wide association studies (GWASs) of educational attainment (n = 1,131,881) and cognitive test performance (n = 257,841) to estimate SNP associations with educational attainment variation that is independent of cognitive ability. We identified 157 genome-wide-significant loci and a polygenic architecture accounting for 57% of genetic variance in educational attainment. Noncognitive genetics were enriched in the same brain tissues and cell types as cognitive performance, but showed different associations with gray-matter brain volumes. Noncognitive genetics were further distinguished by associations with personality traits, less risky behavior and increased risk for certain psychiatric disorders. For socioeconomic success and longevity, noncognitive and cognitive-performance genetics demonstrated associations of similar magnitude. By conducting a GWAS of a phenotype that was not directly measured, we offer a view of genetic architecture of noncognitive skills influencing educational success.
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http://dx.doi.org/10.1038/s41588-020-00754-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116735PMC
January 2021

Illicit drug use and the genetic overlap with Cannabis use.

Drug Alcohol Depend 2020 Jun 10;213:108102. Epub 2020 Jun 10.

Amsterdam UMC, location AMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.

Background: The use of illicit substances is correlated, meaning that individuals who use one illicit substance are more likely to also use another illicit substance. This association could (partly) be explained by overlapping genetic factors. Genetic overlap may indicate a common underlying genetic predisposition, or can be the result of a causal association.

Methods: Polygenic scores for lifetime cannabis use were generated in a sample of Dutch participants (N = 8348). We tested the association of a PGS for cannabis use with ecstasy, stimulants and a broad category of illicit drug use. To explore the nature of the relationship: (1) these analyses were repeated separately in cannabis users and non-users and (2) monozogytic twin pairs discordant for cannabis use were compared on their drug use.

Results: The lifetime prevalence was 24.8 % for cannabis, 6.2 % for ecstasy, 6.5 % for stimulants and 7.1 % for any illicit drug use. Significant, positive associations were found between PGS for cannabis use with ecstasy use, stimulants and any illicit drug use. These associations seemed to be stronger in cannabis users compared to non-users for both ecstasy and stimulant use, but only in people born after 1968 and not significant after correction for multiple testing. The discordant twin pair analyses suggested that cannabis use could play a causal role in drug use.

Conclusions: The genetic liability underlying cannabis use significantly explained variability in ecstasy, stimulant and any illicit drug use. Further research should further explore the underlying mechanism to understand the nature of the association.
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http://dx.doi.org/10.1016/j.drugalcdep.2020.108102DOI Listing
June 2020

Bidirectional effects between loneliness, smoking and alcohol use: evidence from a Mendelian randomization study.

Addiction 2021 02 29;116(2):400-406. Epub 2020 Jun 29.

Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

Background And Aims: Loneliness is associated with cigarette smoking and problematic alcohol use. Observational evidence suggests these associations arise because loneliness increases substance use; however, there is potential for reverse causation (problematic drinking damages social networks, leading to loneliness). With conventional epidemiological methods, controlling for (residual) confounding and reverse causality is difficult. This study applied Mendelian randomization (MR) to assess bidirectional causal effects among loneliness, smoking behaviour and alcohol (mis)use. MR uses genetic variants as instrumental variables to estimate the causal effect of an exposure on an outcome, if the assumptions are satisfied.

Design: Our primary method was inverse-variance weighted (IVW) regression and the robustness of these findings was assessed with five different sensitivity methods.

Setting: European ancestry.

Participants: Summary-level data were drawn from the largest available independent genome-wide association studies (GWAS) of loneliness (n = 511 280), smoking (initiation (n = 249 171), cigarettes per day (n = 249 171) and cessation (n = 143 852), alcoholic drinks per week (n = 226 223) and alcohol dependence (n = 46 568).

Measurements: Genetic variants predictive of the exposure variable were selected as instruments from the respective GWAS.

Findings: There was weak evidence of increased loneliness leading to higher likelihood of initiating smoking, smoking more cigarettes, and a lower likelihood of quitting smoking. Additionally, there was evidence that initiating smoking increases loneliness [IVW, β = 0.30, 95% confidence interval (CI) = 0.22-0.38, P = 2.8 × 10 ]. We found no clear evidence for a causal effect of loneliness on drinks per week (IVW, β = 0.01, 95% CI = -0.11, 0.13, P = 0.865) or alcohol dependence (IVW, β = 0.09, 95% CI = -0.19, 0.36, P = 0.533) nor of alcohol use on loneliness (drinks per week IVW, β = 0.09, 95% CI = -0.02, 0.22, P = 0.076; alcohol dependence IVW, β = 0.06, 95% CI = -0.02, 0.13, P  =  0.162).

Conclusions: There appears to be tentative evidence for causal, bidirectional, increasing effects between loneliness and cigarette smoking, especially for smoking initiation increasing loneliness.
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http://dx.doi.org/10.1111/add.15142DOI Listing
February 2021

Substance use: Interplay between polygenic risk and neighborhood environment.

Drug Alcohol Depend 2020 04 28;209:107948. Epub 2020 Feb 28.

Behavioural Science Institute, Radboud University Nijmegen, the Netherlands.

Background: Tobacco, alcohol, and cannabis use are prevalent behaviors that pose considerable health risks. Genetic vulnerability and characteristics of the neighborhood of residence form important risk factors for substance use. Possibly, these factors do not act in isolation. This study tested the interaction between neighborhood characteristics and genetic risk (gene-environment interaction, GxE) and the association between these classes of risk factors (gene-environment correlation, rGE) in substance use.

Methods: Two polygenic scores (PGS) each (based on different discovery datasets) were created for smoking initiation, cigarettes per day, and glasses of alcohol per week based on summary statistics of different genome-wide association studies (GWAS). For cannabis initiation one PGS was created. These PGS were used to predict their respective phenotype in a large population-based sample from the Netherlands Twin Register (N = 6,567). Neighborhood characteristics as retrieved from governmental registration systems were factor analyzed and resulting measures of socioeconomic status (SES) and metropolitanism were used as predictors.

Results: There were (small) main effects of neighborhood characteristics and PGS on substance use. One of the 14 tested GxE effects was significant, such that the PGS was more strongly associated with alcohol use in individuals with high SES. This was effect was only significant for one out of two PGS. There were weak indications of rGE, mainly with age and cohort covariates.

Conclusion: We conclude that both genetic and neighborhood-level factors are predictors for substance use. More research is needed to establish the robustness of the findings on the interplay between these factors.
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http://dx.doi.org/10.1016/j.drugalcdep.2020.107948DOI Listing
April 2020

Heritability estimates for 361 blood metabolites across 40 genome-wide association studies.

Nat Commun 2020 01 7;11(1):39. Epub 2020 Jan 7.

Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Metabolomics examines the small molecules involved in cellular metabolism. Approximately 50% of total phenotypic differences in metabolite levels is due to genetic variance, but heritability estimates differ across metabolite classes. We perform a review of all genome-wide association and (exome-) sequencing studies published between November 2008 and October 2018, and identify >800 class-specific metabolite loci associated with metabolite levels. In a twin-family cohort (N = 5117), these metabolite loci are leveraged to simultaneously estimate total heritability (h), and the proportion of heritability captured by known metabolite loci (h) for 309 lipids and 52 organic acids. Our study reveals significant differences in h among different classes of lipids and organic acids. Furthermore, phosphatidylcholines with a high degree of unsaturation have higher h estimates than phosphatidylcholines with low degrees of unsaturation. This study highlights the importance of common genetic variants for metabolite levels, and elucidates the genetic architecture of metabolite classes.
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http://dx.doi.org/10.1038/s41467-019-13770-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946682PMC
January 2020

Genetic risk for major depressive disorder and loneliness in sex-specific associations with coronary artery disease.

Mol Psychiatry 2019 Dec 3. Epub 2019 Dec 3.

Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Major depressive disorder (MDD) and loneliness are phenotypically and genetically correlated with coronary artery disease (CAD), but whether these associations are explained by pleiotropic genetic variants or shared comorbidities is unclear. To tease apart these scenarios, we first assessed the medical morbidity pattern associated with genetic risk factors for MDD and loneliness by conducting a phenome-wide association study in 18,385 European-ancestry individuals in the Vanderbilt University Medical Center biobank, BioVU. Polygenic scores for MDD and loneliness were developed for each person using previously published meta-GWAS summary statistics, and were tested for association with 882 clinical diagnoses ascertained via billing codes in electronic health records. We discovered strong associations with heart disease diagnoses, and next embarked on targeted analyses of CAD in 3893 cases and 4197 controls. We found odds ratios of 1.11 (95% CI, 1.04-1.18; P 8.43 × 10) and 1.13 (95% CI, 1.07-1.20; P 4.51 × 10) per 1-SD increase in the polygenic scores for MDD and loneliness, respectively. Results were similar in patients without psychiatric symptoms, and the increased risk persisted in females even after adjusting for multiple conventional risk factors and a polygenic score for CAD. In a final sensitivity analysis, we statistically adjusted for the genetic correlation between MDD and loneliness and re-computed polygenic scores. The polygenic score unique to loneliness remained associated with CAD (OR 1.09, 95% CI 1.03-1.15; P 0.002), while the polygenic score unique to MDD did not (OR 1.00, 95% CI 0.95-1.06; P 0.97). Our replication sample was the Atherosclerosis Risk in Communities (ARIC) cohort of 7197 European-ancestry participants (1598 incident CAD cases). In ARIC, polygenic scores for MDD and loneliness were associated with hazard ratios of 1.07 (95% CI, 0.99-1.14; P = 0.07) and 1.07 (1.01-1.15; P = 0.03), respectively, and we replicated findings from the BioVU sensitivity analyses. We conclude that genetic risk factors for MDD and loneliness act pleiotropically to increase CAD risk in females.
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http://dx.doi.org/10.1038/s41380-019-0614-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266730PMC
December 2019

Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition.

JAMA Psychiatry 2020 04;77(4):420-430

Department of Biological Psychology and Netherlands Twin Register, VU University Amsterdam, Amsterdam, the Netherlands.

Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities.

Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance.

Design, Setting, And Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019.

Main Outcomes And Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort.

Results: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks.

Conclusions And Relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.
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http://dx.doi.org/10.1001/jamapsychiatry.2019.3779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822096PMC
April 2020

Genetic correlates of social stratification in Great Britain.

Nat Hum Behav 2019 12 21;3(12):1332-1342. Epub 2019 Oct 21.

Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.

Human DNA polymorphisms vary across geographic regions, with the most commonly observed variation reflecting distant ancestry differences. Here we investigate the geographic clustering of common genetic variants that influence complex traits in a sample of ~450,000 individuals from Great Britain. Of 33 traits analysed, 21 showed significant geographic clustering at the genetic level after controlling for ancestry, probably reflecting migration driven by socioeconomic status (SES). Alleles associated with educational attainment (EA) showed the most clustering, with EA-decreasing alleles clustering in lower SES areas such as coal mining areas. Individuals who leave coal mining areas carry more EA-increasing alleles on average than those in the rest of Great Britain. The level of geographic clustering is correlated with genetic associations between complex traits and regional measures of SES, health and cultural outcomes. Our results are consistent with the hypothesis that social stratification leaves visible marks in geographic arrangements of common allele frequencies and gene-environment correlations.
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http://dx.doi.org/10.1038/s41562-019-0757-5DOI Listing
December 2019

Phenome-wide investigation of health outcomes associated with genetic predisposition to loneliness.

Hum Mol Genet 2019 11;28(22):3853-3865

Department of Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands.

Humans are social animals that experience intense suffering when they perceive a lack of social connection. Modern societies are experiencing an epidemic of loneliness. Although the experience of loneliness is universally human, some people report experiencing greater loneliness than others. Loneliness is more strongly associated with mortality than obesity, emphasizing the need to understand the nature of the relationship between loneliness and health. Although it is intuitive that circumstantial factors such as marital status and age influence loneliness, there is also compelling evidence of a genetic predisposition toward loneliness. To better understand the genetic architecture of loneliness and its relationship with associated outcomes, we extended the genome-wide association study meta-analysis of loneliness to 511 280 subjects, and detect 19 significant genetic variants from 16 loci, including four novel loci, as well as 58 significantly associated genes. We investigated the genetic overlap with a wide range of physical and mental health traits by computing genetic correlations and by building loneliness polygenic scores in an independent sample of 18 498 individuals with EHR data to conduct a PheWAS with. A genetic predisposition toward loneliness was associated with cardiovascular, psychiatric, and metabolic disorders and triglycerides and high-density lipoproteins. Mendelian randomization analyses showed evidence of a causal, increasing, the effect of both BMI and body fat on loneliness. Our results provide a framework for future studies of the genetic basis of loneliness and its relationship to mental and physical health.
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http://dx.doi.org/10.1093/hmg/ddz219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935385PMC
November 2019

Large-scale GWAS reveals insights into the genetic architecture of same-sex sexual behavior.

Science 2019 08;365(6456)

Centre for Psychology and Evolution, School of Psychology, University of Queensland, St. Lucia, Brisbane QLD 4072, Australia.

Twin and family studies have shown that same-sex sexual behavior is partly genetically influenced, but previous searches for specific genes involved have been underpowered. We performed a genome-wide association study (GWAS) on 477,522 individuals, revealing five loci significantly associated with same-sex sexual behavior. In aggregate, all tested genetic variants accounted for 8 to 25% of variation in same-sex sexual behavior, only partially overlapped between males and females, and do not allow meaningful prediction of an individual's sexual behavior. Comparing these GWAS results with those for the proportion of same-sex to total number of sexual partners among nonheterosexuals suggests that there is no single continuum from opposite-sex to same-sex sexual behavior. Overall, our findings provide insights into the genetics underlying same-sex sexual behavior and underscore the complexity of sexuality.
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http://dx.doi.org/10.1126/science.aat7693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082777PMC
August 2019

Author Correction: GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability.

Nat Neurosci 2019 Jul;22(7):1196

Department of Youth and Family, Utrecht University, Utrecht, the Netherlands.

Several occurrences of the word 'schizophrenia' have been re-worded as 'liability to schizophrenia' or 'schizophrenia risk', including in the title, which should have been "GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability," as well as in Supplementary Figures 1-10 and Supplementary Tables 7-10, to more accurately reflect the findings of the work.
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http://dx.doi.org/10.1038/s41593-019-0402-7DOI Listing
July 2019

Genome-wide Burden of Rare Short Deletions Is Enriched in Major Depressive Disorder in Four Cohorts.

Biol Psychiatry 2019 06 13;85(12):1065-1073. Epub 2019 Mar 13.

Department of Biological Psychology, Amsterdam Public Health Research Institute, Amsterdam, the Netherlands.

Background: Major depressive disorder (MDD) is moderately heritable, with a high prevalence and a presumed high heterogeneity. Copy number variants (CNVs) could contribute to the heritable component of risk, but the two previous genome-wide association studies of rare CNVs did not report significant findings.

Methods: In this meta-analysis of four cohorts (5780 patients and 6626 control subjects), we analyzed the association of MDD to 1) genome-wide burden of rare deletions and duplications, partitioned by length (<100 kb or >100 kb) and other characteristics, and 2) individual rare exonic CNVs and CNV regions.

Results: Patients with MDD carried significantly more short deletions than control subjects (p = .0059) but not long deletions or short or long duplications. The confidence interval for long deletions overlapped with that for short deletions, but long deletions were 70% less frequent genome-wide, reducing the power to detect increased burden. The increased burden of short deletions was primarily in intergenic regions. Short deletions in cases were also modestly enriched for high-confidence enhancer regions. No individual CNV achieved thresholds for suggestive or significant association after genome-wide correction. p values < .01 were observed for 15q11.2 duplications (TUBGCP5, CYFIP1, NIPA1, and NIPA2), deletions in or near PRKN or MSR1, and exonic duplications of ATG5.

Conclusions: The increased burden of short deletions in patients with MDD suggests that rare CNVs increase the risk of MDD by disrupting regulatory regions. Results for longer deletions were less clear, but no large effects were observed for long multigenic CNVs (as seen in schizophrenia and autism). Further studies with larger sample sizes are warranted.
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http://dx.doi.org/10.1016/j.biopsych.2019.02.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750266PMC
June 2019

Biological insights into multiple birth: genetic findings from UK Biobank.

Eur J Hum Genet 2019 06 13;27(6):970-979. Epub 2019 Feb 13.

Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit, Amsterdam, The Netherlands.

The tendency to conceive spontaneous dizygotic (DZ) twins is a complex trait with important contributions from both environmental factors and genetic disposition. In earlier work, we identified the first two genes as maternal susceptibility loci for DZ twinning. The aim of this study was to identify genetic variants influencing multiple births and to genetically correlate the findings across a broad range of traits. We performed a genome-wide association study (GWAS) in 8962 participants with Caucasian ancestry from UK Biobank who reported being part of a multiple birth, and 409,591 singleton controls. We replicated the association between FSHB, SMAD3 and twinning in the gene-based (but not SNP-based) test, which had been established in previous genome-wide association analyses in mothers with dizygotic twin offspring. Additionally, we report a novel genetic variant associated with multiple birth, rs428022 at 15q23 (p = 2.84 × 10) close to two genes: PIAS1 and SKOR1. Finally, we identified meaningful genetic correlations between being part of a multiple birth and other phenotypes (anthropometric traits, health-related traits, and fertility-related measures). The outcomes of this study provide important new insights into the genetic aetiology of multiple births and fertility, and open up novel directions for fertility and reproduction research.
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http://dx.doi.org/10.1038/s41431-019-0355-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777609PMC
June 2019

Correction: Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia.

Mol Psychiatry 2020 Mar;25(3):692-695

Department of Psychiatry and Mental Health, Anzio Road, 7925, Cape Town, South Africa.

Prior to and following the publication of this article the authors noted that the complete list of authors was not included in the main article and was only present in Supplementary Table 1. The author list in the original article has now been updated to include all authors, and Supplementary Table 1 has been removed. All other supplementary files have now been updated accordingly. Furthermore, in Table 1 of this Article, the replication cohort for the row Close relative in data set, n (%) was incorrect. All values have now been corrected to 0(0%). The publishers would like to apologise for this error and the inconvenience it may have caused.
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http://dx.doi.org/10.1038/s41380-019-0358-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608381PMC
March 2020

Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences.

Nat Genet 2019 02 14;51(2):245-257. Epub 2019 Jan 14.

Team Loyalty BV, Hoofddorp, the Netherlands.

Humans vary substantially in their willingness to take risks. In a combined sample of over 1 million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. Across all GWAS, we identified hundreds of associated loci, including 99 loci associated with general risk tolerance. We report evidence of substantial shared genetic influences across risk tolerance and the risky behaviors: 46 of the 99 general risk tolerance loci contain a lead SNP for at least one of our other GWAS, and general risk tolerance is genetically correlated ([Formula: see text] ~ 0.25 to 0.50) with a range of risky behaviors. Bioinformatics analyses imply that genes near SNPs associated with general risk tolerance are highly expressed in brain tissues and point to a role for glutamatergic and GABAergic neurotransmission. We found no evidence of enrichment for genes previously hypothesized to relate to risk tolerance.
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http://dx.doi.org/10.1038/s41588-018-0309-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713272PMC
February 2019

Multivariate genome-wide analyses of the well-being spectrum.

Nat Genet 2019 03 14;51(3):445-451. Epub 2019 Jan 14.

Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.

We introduce two novel methods for multivariate genome-wide-association meta-analysis (GWAMA) of related traits that correct for sample overlap. A broad range of simulation scenarios supports the added value of our multivariate methods relative to univariate GWAMA. We applied the novel methods to life satisfaction, positive affect, neuroticism, and depressive symptoms, collectively referred to as the well-being spectrum (N = 2,370,390), and found 304 significant independent signals. Our multivariate approaches resulted in a 26% increase in the number of independent signals relative to the four univariate GWAMAs and in an ~57% increase in the predictive power of polygenic risk scores. Supporting transcriptome- and methylome-wide analyses (TWAS and MWAS, respectively) uncovered an additional 17 and 75 independent loci, respectively. Bioinformatic analyses, based on gene expression in brain tissues and cells, showed that genes differentially expressed in the subiculum and GABAergic interneurons are enriched in their effect on the well-being spectrum.
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http://dx.doi.org/10.1038/s41588-018-0320-8DOI Listing
March 2019

Epigenome-wide association study of serum cotinine in current smokers reveals novel genetically driven loci.

Clin Epigenetics 2019 01 5;11(1). Epub 2019 Jan 5.

Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.

Background: DNA methylation alteration extensively associates with smoking and is a plausible link between smoking and adverse health. We examined the association between epigenome-wide DNA methylation and serum cotinine levels as a proxy of nicotine exposure and smoking quantity, assessed the role of SNPs in these associations, and evaluated molecular mediation by methylation in a sample of biochemically verified current smokers (N = 310).

Results: DNA methylation at 50 CpG sites was associated (FDR < 0.05) with cotinine levels, 17 of which are novel associations. As cotinine levels are influenced not only by nicotine intake but also by CYP2A6-mediated nicotine metabolism rate, we performed secondary analyses adjusting for genetic risk score of nicotine metabolism rate and identified five additional novel associations. We further assessed the potential role of genetic variants in the detected association between methylation and cotinine levels observing 124 cis and 3898 trans methylation quantitative trait loci (meQTLs). Nineteen of these SNPs were also associated with cotinine levels (FDR < 0.05). Further, at seven CpG sites, we observed a trend (P < 0.05) that altered DNA methylation mediates the effect of SNPs on nicotine exposure rather than a direct consequence of smoking. Finally, we performed replication of our findings in two independent cohorts of biochemically verified smokers (N = 450 and N = 79).

Conclusions: Using cotinine, a biomarker of nicotine exposure, we replicated and extended identification of novel epigenetic associations in smoking-related genes. We also demonstrated that DNA methylation in some of the identified loci is driven by the underlying genotype and may mediate the causal effect of genotype on cotinine levels.
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http://dx.doi.org/10.1186/s13148-018-0606-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321663PMC
January 2019

Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia.

Mol Psychiatry 2020 03 3;25(3):584-602. Epub 2018 Oct 3.

Department of Psychiatry and Mental Health, Anzio Road, 7925, Cape Town, South Africa.

Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = -0.71 to -1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = -0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10, 1.7 × 10, 3.5 × 10 and 1.0 × 10, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.
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http://dx.doi.org/10.1038/s41380-018-0118-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042770PMC
March 2020

GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia.

Nat Neurosci 2018 09 27;21(9):1161-1170. Epub 2018 Aug 27.

Department of Youth and Family, Utrecht University, Utrecht, the Netherlands.

Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), we identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2, which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested substance use and mental health-related traits, including smoking, alcohol use, schizophrenia and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use. Overall, our study provides new insights into the etiology of cannabis use and its relation with mental health.
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http://dx.doi.org/10.1038/s41593-018-0206-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386176PMC
September 2018
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