Biology subjects

Nolte, I. M.

Publications and source records attributed to Nolte, I. M..

8 recordsLinked to original sources

bioRxiv2025

Genome-wide analysis of social behaviour in context: a meta-regression approach across social domains, reporters and developmental stages

Social behaviour is a heritable, context-dependent trait that changes across social settings and development, influencing wellbeing and mental health. We present the first genome-wide meta-regression study of social behaviour from infancy to early adulthood, leveraging 491,246 repeat measures of low prosocial behaviour and peer/social difficulties in European-ancestry cohorts (Neff=121,777, Nind=73,321). We modelled heterogeneity in genetic effects across social domains, informants, and ages (2-29 years), capturing social context through genomic influences. Six loci were identified, including variation within CADM2 (p=2.51x10-9). The SNP-based heritability was modest (2-7%), and the genetic architecture of social behaviour multidimensional. Polygenic scores demonstrated predictability and accuracy in independent European-ancestry cohorts and, partially, in African-ancestry cohorts (Nind=16,305). Genetic correlations with later-life and mental health outcomes showed context-dependent patterns. Modelling predicted onsets of associations with social behaviour revealed distinct profiles, as observed for autism, ADHD, depression and schizophrenia, highlighting novel opportunities to genetically proxy developmental trajectories.

genomics↗

bioRxiv2022

Leveraging functional genomic annotations and genome coverage to improve polygenic prediction of complex traits within and between ancestries

We develop a new method, SBayesRC, that integrates GWAS summary statistics with functional genomic annotations to improve polygenic prediction of complex traits. Our method is scalable to whole-genome variant analysis and refines signals from functional annotations by allowing them to affect both causal variant probability and causal effect distribution. We analyse 28 traits in the UK Biobank using [~]7 million common SNPs and 96 annotations. SBayesRC improves prediction accuracy by 14% in European ancestry and by up to 33% in trans-ancestry prediction, compared to the baseline method SBayesR which does not use annotations, and outperforms state-of-the-art methods LDpred-funct, PolyPred-S and PRS-CSx by 12-15%. Investigation of factors affecting prediction accuracy identified a significant interaction between SNP density and annotation information, encouraging future use of whole-genome sequence variants for prediction. Functional partitioning analysis highlights a major contribution of evolutionary constrained regions to prediction accuracy and the largest per-SNP contribution from non-synonymous SNPs.

genetics↗

bioRxiv2021

Uncovering the Genetic Architecture of Broad Antisocial Behavior through a Genome-Wide Association Study Meta-analysis.

Despite the substantial heritability of antisocial behavior (ASB), specific genetic variants robustly associated with the trait have not been identified. The present study by the Broad Antisocial Behavior Consortium (BroadABC) meta-analyzed data from 28 discovery samples (N = 85,359) and five independent replication samples (N = 8,058) with genotypic data and broad measures of ASB. We identified the first significant genetic associations with broad ASB, involving common intronic variants in the forkhead box protein P2 (FOXP2) gene (lead SNP rs12536335, P = 6.32 x 10-10). Furthermore, we observed intronic variation in Foxp2 and one of its targets (Cntnap2) distinguishing a mouse model of pathological aggression (BALB/cJ strain) from controls (BALB/cByJ strain). The SNP-based heritability of ASB was 8.4% (s.e.= 1.2%). Polygenic-risk-score (PRS) analyses in independent samples revealed that the genetic risk for ASB was associated with several antisocial outcomes across the lifespan, including diagnosis of conduct disorder, official criminal convictions, and trajectories of antisocial development. We found substantial genetic correlations of ASB with mental health (depression rg{square}={square}0.63, insomnia rg = 0.47), physical health (overweight rg = 0.19, waist-to-hip ratio rg = 0.32), smoking (rg{square}={square}0.54), cognitive ability (intelligence rg= -0.40), educational attainment (years of schooling rg = -0.46) and reproductive traits (age at first birth rg={square}- 0.58, fathers age at death rg= -0.54). Our findings provide a starting point towards identifying critical biosocial risk mechanisms for the development of ASB.

genetics↗

bioRxiv2020

Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups using 1 degree of freedom (1df) interaction and 2df joint tests. Primary multi-ancestry analyses in 62,969 individuals in stage 1 identified 3 novel loci that were replicated in an additional 59,296 individuals in stage 2, including rs7955964 (FIGNL2/ANKRD33) showing significant 1df interactions with long sleep duration and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) showing significant 1df interactions with short sleep duration (Pint < 5x10-8). Secondary ancestry-specific two-stage analyses and combined stage 1 and 2 analyses additionally identified 23 novel loci that need external replication, including 3 and 5 loci showing significant 1df interactions with long and short sleep duration, respectively (Pint < 5x10-8). Multiple genes mapped to our 26 novel loci have known functions in sleep-wake regulation, nervous and cardiometabolic systems. We also identified new gene by long sleep interactions near five known BP loci ([≤]1Mb) including NME7, FAM208A, MKLN1, CEP164, and RGL3/ELAVL3 (Pint < 5x10-8). This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.

genomics↗

bioRxiv2019

Genetic Association Study of Childhood Aggression across raters, instruments and age

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data - i.e. within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE=0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P=1.6E-06), PCDH7 (P=2.0E-06) and IPO13 (P=2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg =0.46 between self- and teacher-assessment to rg =0.81 between mother- and teacher-assessment. We obtained moderate to strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range |rg| : 0.19 - 1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg =~ -0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range |rg| : 0.46 - 0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.

genomics↗

bioRxiv2019

KCND3 is a novel susceptibility locus for early repolarization

The presence of an early repolarization pattern (ERP) on the surface electrocardiogram (ECG) is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have shown that ERP is a highly heritable trait but molecular genetic determinants are unknown. We assessed the ERP in 12-lead ECGs of 39,456 individuals and conducted a two-stage meta-analysis of genome-wide association studies (GWAS). In the discovery phase, we included 2,181 cases and 23,641 controls from eight European ancestry studies and identified 19 genome-wide significant (p<5E-8) variants in the KCND3 (potassium voltage gated channel subfamily D member 3) gene with a p-value of 4.6E-10. Replication of two loci in four additional studies including 1,124 cases and 12,510 controls confirmed the association at the KCND3 gene locus with a pooled odds ratio of 0.82, p=7.7E-12 (rs1545300 minor allele T). A subsequent GWAS meta-analysis combining all samples did not reveal additional loci. The lead SNP of the discovery stage (rs12090194) was in strong linkage disequilibrium with rs1545300 (r2=0.96, D=1). Summary statistics based conditional analysis did not reveal any secondary signals. Co-localization analyses indicate causal effects of KCND3 gene expression levels on ERP in both the left ventricle of the heart and in tibial artery.\n\nIn this study we identified for the first time a genome-wide significant association of a genetic variant with ERP. Our findings of a locus in the KCND3 gene not only provide insights into the genetic determinants but also into the pathophysiological mechanism of ERP, revealing a promising candidate for functional studies.

genetics↗

bioRxiv2018

Genome-wide association and functional studies identify 46 novel loci for alcohol consumption and suggest common genetic mechanisms with neuropsychiatric disorders

Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. We conducted a genome-wide association study (GWAS) of alcohol use in ~480,000 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 novel, common loci, and investigated their potential functional significance using magnetic resonance imaging data, gene expression and behavioral studies in Drosophila. Our results identify new genetic pathways associated with alcohol consumption and suggest common genetic mechanisms with several neuropsychiatric disorders including schizophrenia.

genetics↗

bioRxiv2018

Genome-wide association meta-analysis of PR interval identifies 47 novel loci associated with atrial and atrioventricular electrical activity

Electrocardiographic PR interval measures atrial and atrioventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. We performed a genome-wide association study in over 92,000 individuals of European descent and identified 44 loci associated with PR interval (34 novel). Examination of the 44 loci revealed known and novel biological processes involved in cardiac atrial electrical activity, and genes in these loci were highly over-represented in several cardiac disease processes. Nearly half of the 61 independent index variants in the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with one or more missense variants. Cardiac regulatory regions of the genome as measured by cardiac DNA hypersensitivity sites were enriched for variants associated with PR interval, compared to non-cardiac regulatory regions. Joint analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation identified additional new pleiotropic loci. The majority of associations discovered in European-descent populations were also present in African-American populations. Meta-analysis examining over 105,000 individuals of African and European descent identified additional novel PR loci. These additional analyses identified another 13 novel loci. Together, these findings underscore the power of GWAS to extend knowledge of the molecular underpinnings of clinical processes.

genetics↗