Publications by authors named "Beate St Pourcain"

101 Publications

Multivariate genome-wide covariance analyses of literacy, language and working memory skills reveal distinct etiologies.

NPJ Sci Learn 2021 Aug 19;6(1):23. Epub 2021 Aug 19.

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Several abilities outside literacy proper are associated with reading and spelling, both phenotypically and genetically, though our knowledge of multivariate genomic covariance structures is incomplete. Here, we introduce structural models describing genetic and residual influences between traits to study multivariate links across measures of literacy, phonological awareness, oral language, and phonological working memory (PWM) in unrelated UK youth (8-13 years, N = 6453). We find that all phenotypes share a large proportion of underlying genetic variation, although especially oral language and PWM reveal substantial differences in their genetic variance composition with substantial trait-specific genetic influences. Multivariate genetic and residual trait covariance showed concordant patterns, except for marked differences between oral language and literacy/phonological awareness, where strong genetic links contrasted near-zero residual overlap. These findings suggest differences in etiological mechanisms, acting beyond a pleiotropic set of genetic variants, and implicate variation in trait modifiability even among phenotypes that have high genetic correlations.
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http://dx.doi.org/10.1038/s41539-021-00101-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377061PMC
August 2021

Genetic association study of childhood aggression across raters, instruments, and age.

Transl Psychiatry 2021 07 30;11(1):413. Epub 2021 Jul 30.

Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

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 (AGG) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGG. 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 (r) among rater-specific assessment of AGG ranged from r = 0.46 between self- and teacher-assessment to r = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rs 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 [Formula: see text]: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (r = ~-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range [Formula: see text]: 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.
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http://dx.doi.org/10.1038/s41398-021-01480-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324785PMC
July 2021

Developmental trajectories of autistic social traits in the general population.

Psychol Med 2021 Jun 22:1-9. Epub 2021 Jun 22.

University College London, Research Department of Clinical, Educational and Health Psychology, 1-19 Torrington Place, LondonWC1E 7HB, UK.

Background: Autistic people show diverse trajectories of autistic traits over time, a phenomenon labelled 'chronogeneity'. For example, some show a decrease in symptoms, whilst others experience an intensification of difficulties. Autism spectrum disorder (ASD) is a dimensional condition, representing one end of a trait continuum that extends throughout the population. To date, no studies have investigated chronogeneity across the full range of autistic traits. We investigated the nature and clinical significance of autism trait chronogeneity in a large, general population sample.

Methods: Autistic social/communication traits (ASTs) were measured in the Avon Longitudinal Study of Parents and Children using the Social and Communication Disorders Checklist (SCDC) at ages 7, 10, 13 and 16 (N = 9744). We used Growth Mixture Modelling (GMM) to identify groups defined by their AST trajectories. Measures of ASD diagnosis, sex, IQ and mental health (internalising and externalising) were used to investigate external validity of the derived trajectory groups.

Results: The selected GMM model identified four AST trajectory groups: (i) Persistent High (2.3% of sample), (ii) Persistent Low (83.5%), (iii) Increasing (7.3%) and (iv) Decreasing (6.9%) trajectories. The Increasing group, in which females were a slight majority (53.2%), showed dramatic increases in SCDC scores during adolescence, accompanied by escalating internalising and externalising difficulties. Two-thirds (63.6%) of the Decreasing group were male.

Conclusions: Clinicians should note that for some young people autism-trait-like social difficulties first emerge during adolescence accompanied by problems with mood, anxiety, conduct and attention. A converse, majority-male group shows decreasing social difficulties during adolescence.
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http://dx.doi.org/10.1017/S0033291721002166DOI Listing
June 2021

The developmental genetic architecture of vocabulary skills during the first three years of life: Capturing emerging associations with later-life reading and cognition.

PLoS Genet 2021 02 12;17(2):e1009144. Epub 2021 Feb 12.

Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.

Individual differences in early-life vocabulary measures are heritable and associated with subsequent reading and cognitive abilities, although the underlying mechanisms are little understood. Here, we (i) investigate the developmental genetic architecture of expressive and receptive vocabulary in early-life and (ii) assess timing of emerging genetic associations with mid-childhood verbal and non-verbal skills. We studied longitudinally assessed early-life vocabulary measures (15-38 months) and later-life verbal and non-verbal skills (7-8 years) in up to 6,524 unrelated children from the population-based Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. We dissected the phenotypic variance of rank-transformed scores into genetic and residual components by fitting multivariate structural equation models to genome-wide genetic-relationship matrices. Our findings show that the genetic architecture of early-life vocabulary involves multiple distinct genetic factors. Two of these genetic factors are developmentally stable and also contribute to genetic variation in mid-childhood skills: One genetic factor emerging with expressive vocabulary at 24 months (path coefficient: 0.32(SE = 0.06)) was also related to later-life reading (path coefficient: 0.25(SE = 0.12)) and verbal intelligence (path coefficient: 0.42(SE = 0.13)), explaining up to 17.9% of the phenotypic variation. A second, independent genetic factor emerging with receptive vocabulary at 38 months (path coefficient: 0.15(SE = 0.07)), was more generally linked to verbal and non-verbal cognitive abilities in mid-childhood (reading path coefficient: 0.57(SE = 0.07); verbal intelligence path coefficient: 0.60(0.10); performance intelligence path coefficient: 0.50(SE = 0.08)), accounting for up to 36.1% of the phenotypic variation and the majority of genetic variance in these later-life traits (≥66.4%). Thus, the genetic foundations of mid-childhood reading and cognitive abilities are diverse. They involve at least two independent genetic factors that emerge at different developmental stages during early language development and may implicate differences in cognitive processes that are already detectable during toddlerhood.
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http://dx.doi.org/10.1371/journal.pgen.1009144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880480PMC
February 2021

Genome-wide association study of circulating interleukin 6 levels identifies novel loci.

Hum Mol Genet 2021 04;30(5):393-409

Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK.

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
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http://dx.doi.org/10.1093/hmg/ddab023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098112PMC
April 2021

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Nat Commun 2021 01 5;12(1):24. Epub 2021 Jan 5.

Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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http://dx.doi.org/10.1038/s41467-020-19366-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785747PMC
January 2021

Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia.

Mol Psychiatry 2021 Jul 14;26(7):3004-3017. Epub 2020 Oct 14.

Department of Cognitive Neuroscience, Faculty of Psychology and Neuroscience and Maastricht Brain Imaging Center (M-BIC), Maastricht University, Maastricht, The Netherlands.

Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40-60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p  < 2.8 × 10) enrichment of associations at the gene level, for LOC388780 (20p13; uncharacterized gene), and for VEPH1 (3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20-25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (at p = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase; p  = 8 × 10), bipolar disorder (1.53[1.44; 1.63]; p = 1 × 10), schizophrenia (1.36[1.28; 1.45]; p = 4 × 10), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30]; p = 3 × 10), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96]; p = 5 × 10), educational attainment (0.86[0.82; 0.91]; p = 2 × 10), and intelligence (0.72[0.68; 0.76]; p = 9 × 10). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence.
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http://dx.doi.org/10.1038/s41380-020-00898-xDOI Listing
July 2021

Genome-wide association study identifies 48 common genetic variants associated with handedness.

Nat Hum Behav 2021 01 28;5(1):59-70. Epub 2020 Sep 28.

Institute of Biological Psychiatry, Mental Health Services of Copenhagen, Copenhagen, Denmark.

Handedness has been extensively studied because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and the International Handedness Consortium, we conducted a genome-wide association meta-analysis of handedness (N = 1,766,671). We found 41 loci associated (P < 5 × 10) with left-handedness and 7 associated with ambidexterity. Tissue-enrichment analysis implicated the CNS in the aetiology of handedness. Pathways including regulation of microtubules and brain morphology were also highlighted. We found suggestive positive genetic correlations between left-handedness and neuropsychiatric traits, including schizophrenia and bipolar disorder. Furthermore, the genetic correlation between left-handedness and ambidexterity is low (r = 0.26), which implies that these traits are largely influenced by different genetic mechanisms. Our findings suggest that handedness is highly polygenic and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders.
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http://dx.doi.org/10.1038/s41562-020-00956-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116623PMC
January 2021

The developmental origins of genetic factors influencing language and literacy: Associations with early-childhood vocabulary.

J Child Psychol Psychiatry 2021 06 14;62(6):728-738. Epub 2020 Sep 14.

Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.

Background: The heritability of language and literacy skills increases from early-childhood to adolescence. The underlying mechanisms are little understood and may involve (a) the amplification of genetic influences contributing to early language abilities, and/or (b) the emergence of novel genetic factors (innovation). Here, we investigate the developmental origins of genetic factors influencing mid-childhood/early-adolescent language and literacy. We evaluate evidence for the amplification of early-childhood genetic factors for vocabulary, in addition to genetic innovation processes.

Methods: Expressive and receptive vocabulary scores at 38 months, thirteen language- and literacy-related abilities and nonverbal cognition (7-13 years) were assessed in unrelated children from the Avon Longitudinal Study of Parents and Children (ALSPAC, N  ≤ 6,092). We investigated the multivariate genetic architecture underlying early-childhood expressive and receptive vocabulary, and each of 14 mid-childhood/early-adolescent language, literacy or cognitive skills with trivariate structural equation (Cholesky) models as captured by genome-wide genetic relationship matrices. The individual path coefficients of the resulting structural models were finally meta-analysed to evaluate evidence for overarching patterns.

Results: We observed little support for the emergence of novel genetic sources for language, literacy or cognitive abilities during mid-childhood or early adolescence. Instead, genetic factors of early-childhood vocabulary, especially those unique to receptive skills, were amplified and represented the majority of genetic variance underlying many of these later complex skills (≤99%). The most predictive early genetic factor accounted for 29.4%(SE = 12.9%) to 45.1%(SE = 7.6%) of the phenotypic variation in verbal intelligence and literacy skills, but also for 25.7%(SE = 6.4%) in performance intelligence, while explaining only a fraction of the phenotypic variation in receptive vocabulary (3.9%(SE = 1.8%)).

Conclusions: Genetic factors contributing to many complex skills during mid-childhood and early adolescence, including literacy, verbal cognition and nonverbal cognition, originate developmentally in early-childhood and are captured by receptive vocabulary. This suggests developmental genetic stability and overarching aetiological mechanisms.
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http://dx.doi.org/10.1111/jcpp.13327DOI Listing
June 2021

Evaluating shared genetic influences on nonsyndromic cleft lip/palate and oropharyngeal neoplasms.

Genet Epidemiol 2020 11 24;44(8):924-933. Epub 2020 Jul 24.

Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, UK.

It has been hypothesised that nonsyndromic cleft lip/palate (nsCL/P) and cancer may share aetiological risk factors. Population studies have found inconsistent evidence for increased incidence of cancer in nsCL/P cases, but several genes (e.g., CDH1, AXIN2) have been implicated in the aetiologies of both phenotypes. We aimed to evaluate shared genetic aetiology between nsCL/P and oral cavity/oropharyngeal cancers (OC/OPC), which affect similar anatomical regions. Using a primary sample of 5,048 OC/OPC cases and 5,450 controls of European ancestry and a replication sample of 750 cases and 336,319 controls from UK Biobank, we estimate genetic overlap using nsCL/P polygenic risk scores (PRS) with Mendelian randomization analyses performed to evaluate potential causal mechanisms. In the primary sample, we found strong evidence for an association between a nsCL/P PRS and increased odds of OC/OPC (per standard deviation increase in score, odds ratio [OR]: 1.09; 95% confidence interval [CI]: 1.04, 1.13; p = .000053). Although confidence intervals overlapped with the primary estimate, we did not find confirmatory evidence of an association between the PRS and OC/OPC in UK Biobank (OR 1.02; 95% CI: 0.95, 1.10; p = .55). Mendelian randomization analyses provided evidence that major nsCL/P risk variants are unlikely to influence OC/OPC. Our findings suggest possible shared genetic influences on nsCL/P and OC/OPC.
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http://dx.doi.org/10.1002/gepi.22343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240308PMC
November 2020

The genetic architecture of the human cerebral cortex.

Science 2020 03;367(6484)

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
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http://dx.doi.org/10.1126/science.aay6690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295264PMC
March 2020

Genetic evidence for assortative mating on alcohol consumption in the UK Biobank.

Nat Commun 2019 11 19;10(1):5039. Epub 2019 Nov 19.

Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, UK.

Alcohol use is correlated within spouse-pairs, but it is difficult to disentangle effects of alcohol consumption on mate-selection from social factors or the shared spousal environment. We hypothesised that genetic variants related to alcohol consumption may, via their effect on alcohol behaviour, influence mate selection. Here, we find strong evidence that an individual's self-reported alcohol consumption and their genotype at rs1229984, a missense variant in ADH1B, are associated with their partner's self-reported alcohol use. Applying Mendelian randomization, we estimate that a unit increase in an individual's weekly alcohol consumption increases partner's alcohol consumption by 0.26 units (95% C.I. 0.15, 0.38; P = 8.20 × 10). Furthermore, we find evidence of spousal genotypic concordance for rs1229984, suggesting that spousal concordance for alcohol consumption existed prior to cohabitation. Although the SNP is strongly associated with ancestry, our results suggest some concordance independent of population stratification. Our findings suggest that alcohol behaviour directly influences mate selection.
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http://dx.doi.org/10.1038/s41467-019-12424-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864067PMC
November 2019

Investigating genetic links between grapheme-colour synaesthesia and neuropsychiatric traits.

Philos Trans R Soc Lond B Biol Sci 2019 12 21;374(1787):20190026. Epub 2019 Oct 21.

Language and Genetics Department, Max Planck Institute for Psycholinguistics, 6525 XD Nijmegen, The Netherlands.

Synaesthesia is a neurological phenomenon affecting perception, where triggering stimuli (e.g. letters and numbers) elicit unusual secondary sensory experiences (e.g. colours). Family-based studies point to a role for genetic factors in the development of this trait. However, the contributions of common genomic variation to synaesthesia have not yet been investigated. Here, we present the SynGenes cohort, the largest genotyped collection of unrelated people with grapheme-colour synaesthesia ( = 723). Synaesthesia has been associated with a range of other neuropsychological traits, including enhanced memory and mental imagery, as well as greater sensory sensitivity. Motivated by the prior literature on putative trait overlaps, we investigated polygenic scores derived from published genome-wide scans of schizophrenia and autism spectrum disorder (ASD), comparing our SynGenes cohort to 2181 non-synaesthetic controls. We found a very slight association between schizophrenia polygenic scores and synaesthesia (Nagelkerke's = 0.0047, empirical = 0.0027) and no significant association for scores related to ASD (Nagelkerke's = 0.00092, empirical = 0.54) or body mass index ( = 0.00058, empirical = 0.60), included as a negative control. As sample sizes for studying common genomic variation continue to increase, genetic investigations of the kind reported here may yield novel insights into the shared biology between synaesthesia and other traits, to complement findings from neuropsychology and brain imaging. This article is part of a discussion meeting issue 'Bridging senses: novel insights from synaesthesia'.
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http://dx.doi.org/10.1098/rstb.2019.0026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834005PMC
December 2019

Identification of common genetic risk variants for autism spectrum disorder.

Nat Genet 2019 03 25;51(3):431-444. Epub 2019 Feb 25.

The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.
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http://dx.doi.org/10.1038/s41588-019-0344-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454898PMC
March 2019

Genome-wide association scan identifies new variants associated with a cognitive predictor of dyslexia.

Transl Psychiatry 2019 02 11;9(1):77. Epub 2019 Feb 11.

School of Life and Health Sciences, Aston University, Birmingham, UK.

Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562-3468). We observed a genome-wide significant effect (p < 1 × 10) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene; rs17663182 p = 4.73 × 10), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p = 2.25 × 10). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 × 10) and with all the cognitive traits tested (p = 3.07 × 10), suggesting (relational) pleiotropic effects of this variant. A polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD. Reading and spelling abilities were positively associated with EDUyears (p ~ [10-10]) and negatively associated with ADHD PRS (p ~ [10-10]). This corroborates a long-standing hypothesis on the partly shared genetic etiology of DD and ADHD, at the genome-wide level. Our findings suggest new candidate DD susceptibility genes and provide new insights into the genetics of dyslexia and its comorbities.
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http://dx.doi.org/10.1038/s41398-019-0402-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370792PMC
February 2019

Disentangling polygenic associations between attention-deficit/hyperactivity disorder, educational attainment, literacy and language.

Transl Psychiatry 2019 01 24;9(1):35. Epub 2019 Jan 24.

Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.

Interpreting polygenic overlap between ADHD and both literacy-related and language-related impairments is challenging as genetic associations might be influenced by indirectly shared genetic factors. Here, we investigate genetic overlap between polygenic ADHD risk and multiple literacy-related and/or language-related abilities (LRAs), as assessed in UK children (N ≤ 5919), accounting for genetically predictable educational attainment (EA). Genome-wide summary statistics on clinical ADHD and years of schooling were obtained from large consortia (N ≤ 326,041). Our findings show that ADHD-polygenic scores (ADHD-PGS) were inversely associated with LRAs in ALSPAC, most consistently with reading-related abilities, and explained ≤1.6% phenotypic variation. These polygenic links were then dissected into both ADHD effects shared with and independent of EA, using multivariable regressions (MVR). Conditional on EA, polygenic ADHD risk remained associated with multiple reading and/or spelling abilities, phonemic awareness and verbal intelligence, but not listening comprehension and non-word repetition. Using conservative ADHD-instruments (P-threshold < 5 × 10), this corresponded, for example, to a 0.35 SD decrease in pooled reading performance per log-odds in ADHD-liability (P = 9.2 × 10). Using subthreshold ADHD-instruments (P-threshold < 0.0015), these effects became smaller, with a 0.03 SD decrease per log-odds in ADHD risk (P = 1.4 × 10), although the predictive accuracy increased. However, polygenic ADHD-effects shared with EA were of equal strength and at least equal magnitude compared to those independent of EA, for all LRAs studied, and detectable using subthreshold instruments. Thus, ADHD-related polygenic links with LRAs are to a large extent due to shared genetic effects with EA, although there is evidence for an ADHD-specific association profile, independent of EA, that primarily involves literacy-related impairments.
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http://dx.doi.org/10.1038/s41398-018-0324-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345874PMC
January 2019

Low-frequency variation in TP53 has large effects on head circumference and intracranial volume.

Nat Commun 2019 01 21;10(1):357. Epub 2019 Jan 21.

School of Medicine and Public Health, Faculty of Medicine and Health, The University of Newcastle, Newcastle, NSW, 2308, Australia.

Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development.
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http://dx.doi.org/10.1038/s41467-018-07863-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341110PMC
January 2019

Evidence for DNA methylation mediating genetic liability to non-syndromic cleft lip/palate.

Epigenomics 2019 02 14;11(2):133-145. Epub 2019 Jan 14.

MRC Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, BS8 2BN, UK.

Aim: To determine if nonsyndromic cleft lip with or without cleft palate (nsCL/P) genetic risk variants influence liability to nsCL/P through gene regulation pathways, such as those involving DNA methylation.

Materials & Methods: nsCL/P genetic summary data and methylation data from four studies were used in conjunction with Mendelian randomization and joint likelihood mapping to investigate potential mediation of nsCL/P genetic variants.

Results & Conclusion: Evidence was found at VAX1 (10q25.3), LOC146880 (17q23.3) and NTN1 (17p13.1), that liability to nsCL/P and variation in DNA methylation might be driven by the same genetic variant, suggesting that genetic variation at these loci may increase liability to nsCL/P by influencing DNA methylation. Follow-up analyses using different tissues and gene expression data provided further insight into possible biological mechanisms.
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http://dx.doi.org/10.2217/epi-2018-0091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462847PMC
February 2019

Neandertal Introgression Sheds Light on Modern Human Endocranial Globularity.

Curr Biol 2019 01 13;29(1):120-127.e5. Epub 2018 Dec 13.

Language and Genetics Department, Max Planck Institute for Psycholinguistics, P.O. Box 310, 6500 AH, Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands. Electronic address:

One of the features that distinguishes modern humans from our extinct relatives and ancestors is a globular shape of the braincase [1-4]. As the endocranium closely mirrors the outer shape of the brain, these differences might reflect altered neural architecture [4, 5]. However, in the absence of fossil brain tissue, the underlying neuroanatomical changes as well as their genetic bases remain elusive. To better understand the biological foundations of modern human endocranial shape, we turn to our closest extinct relatives: the Neandertals. Interbreeding between modern humans and Neandertals has resulted in introgressed fragments of Neandertal DNA in the genomes of present-day non-Africans [6, 7]. Based on shape analyses of fossil skull endocasts, we derive a measure of endocranial globularity from structural MRI scans of thousands of modern humans and study the effects of introgressed fragments of Neandertal DNA on this phenotype. We find that Neandertal alleles on chromosomes 1 and 18 are associated with reduced endocranial globularity. These alleles influence expression of two nearby genes, UBR4 and PHLPP1, which are involved in neurogenesis and myelination, respectively. Our findings show how integration of fossil skull data with archaic genomics and neuroimaging can suggest developmental mechanisms that may contribute to the unique modern human endocranial shape.
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http://dx.doi.org/10.1016/j.cub.2018.10.065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380688PMC
January 2019

Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders.

Am J Hum Genet 2018 11;103(5):691-706

Department of Epidemiology and Prevention, Public Health Sciences, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA.

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.
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http://dx.doi.org/10.1016/j.ajhg.2018.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218410PMC
November 2018

Investigating the shared genetics of non-syndromic cleft lip/palate and facial morphology.

PLoS Genet 2018 08 1;14(8):e1007501. Epub 2018 Aug 1.

Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, United Kingdom.

There is increasing evidence that genetic risk variants for non-syndromic cleft lip/palate (nsCL/P) are also associated with normal-range variation in facial morphology. However, previous analyses are mostly limited to candidate SNPs and findings have not been consistently replicated. Here, we used polygenic risk scores (PRS) to test for genetic overlap between nsCL/P and seven biologically relevant facial phenotypes. Where evidence was found of genetic overlap, we used bidirectional Mendelian randomization (MR) to test the hypothesis that genetic liability to nsCL/P is causally related to implicated facial phenotypes. Across 5,804 individuals of European ancestry from two studies, we found strong evidence, using PRS, of genetic overlap between nsCL/P and philtrum width; a 1 S.D. increase in nsCL/P PRS was associated with a 0.10 mm decrease in philtrum width (95% C.I. 0.054, 0.146; P = 2x10-5). Follow-up MR analyses supported a causal relationship; genetic variants for nsCL/P homogeneously cause decreased philtrum width. In addition to the primary analysis, we also identified two novel risk loci for philtrum width at 5q22.2 and 7p15.2 in our Genome-wide Association Study (GWAS) of 6,136 individuals. Our results support a liability threshold model of inheritance for nsCL/P, related to abnormalities in development of the philtrum.
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http://dx.doi.org/10.1371/journal.pgen.1007501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089455PMC
August 2018

The development of autistic social traits across childhood and adolescence in males and females.

J Child Psychol Psychiatry 2018 11 19;59(11):1143-1151. Epub 2018 Apr 19.

Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Background: Autism is a dimensional condition, representing the extreme end of a continuum of social competence that extends throughout the general population. Currently, little is known about how autistic social traits (ASTs), measured across the full spectrum of severity, develop during childhood and adolescence, including whether there are developmental differences between boys and girls. Therefore, we sought to chart the trajectories of ASTs in the general population across childhood and adolescence, with a focus on gender differences.

Methods: Participants were 9,744 males (n = 4,784) and females (n = 4,960) from ALSPAC, a UK birth cohort study. ASTs were assessed when participants were aged 7, 10, 13 and 16 years, using the parent-report Social Communication Disorders Checklist. Data were modelled using latent growth curve analysis.

Results: Developmental trajectories of males and females were nonlinear, showing a decline from 7 to 10 years, followed by an increase between 10 and 16 years. At 7 years, males had higher levels of ASTs than females (mean raw score difference = 0.88, 95% CI [.72, 1.04]), and were more likely (odds ratio [OR]  = 1.99; 95% CI, 1.82, 2.16) to score in the clinical range on the SCDC. By 16 years this gender difference had disappeared: males and females had, on average, similar levels of ASTs (mean difference = 0.00, 95% CI [-0.19, 0.19]) and were equally likely to score in the SCDC's clinical range (OR = 0.91, 95% CI, 0.73, 1.10). This was the result of an increase in females' ASTs between 10 and 16 years.

Conclusions: There are gender-specific trajectories of autistic social impairment, with females more likely than males to experience an escalation of ASTs during early- and midadolescence. It remains to be discovered whether the observed female adolescent increase in ASTs represents the genuine late onset of social difficulties or earlier, subtle, pre-existing difficulties becoming more obvious.
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http://dx.doi.org/10.1111/jcpp.12913DOI Listing
November 2018

Developmental Changes Within the Genetic Architecture of Social Communication Behavior: A Multivariate Study of Genetic Variance in Unrelated Individuals.

Biol Psychiatry 2018 04 28;83(7):598-606. Epub 2017 Sep 28.

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.

Background: Recent analyses of trait-disorder overlap suggest that psychiatric dimensions may relate to distinct sets of genes that exert maximum influence during different periods of development. This includes analyses of social communication difficulties that share, depending on their developmental stage, stronger genetic links with either autism spectrum disorder or schizophrenia. We developed a multivariate analysis framework in unrelated individuals to model directly the developmental profile of genetic influences contributing to complex traits, such as social communication difficulties, during an approximately 10-year period spanning childhood and adolescence.

Methods: Longitudinally assessed quantitative social communication problems (N ≤ 5551) were studied in participants from a United Kingdom birth cohort (Avon Longitudinal Study of Parents and Children; age range, 8-17 years). Using standardized measures, genetic architectures were investigated with novel multivariate genetic-relationship-matrix structural equation models incorporating whole-genome genotyping information. Analogous to twin research, genetic-relationship-matrix structural equation models included Cholesky decomposition, common pathway, and independent pathway models.

Results: A two-factor Cholesky decomposition model described the data best. One genetic factor was common to Social Communication Disorder Checklist measures across development; the other accounted for independent variation at 11 years and later, consistent with distinct developmental profiles in trait-disorder overlap. Importantly, genetic factors operating at 8 years explained only approximately 50% of genetic variation at 17 years.

Conclusions: Using latent factor models, we identified developmental changes in the genetic architecture of social communication difficulties that enhance the understanding of autism spectrum disorder- and schizophrenia-related dimensions. More generally, genetic-relationship-matrix structural equation models present a framework for modeling shared genetic etiologies between phenotypes and can provide prior information with respect to patterns and continuity of trait-disorder overlap.
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http://dx.doi.org/10.1016/j.biopsych.2017.09.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855319PMC
April 2018

Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits.

Am J Hum Genet 2017 Jun 25;100(6):865-884. Epub 2017 May 25.

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London W2 1PG, UK; Department of Cardiology, Ealing Hospital NHS Trust, Middlesex UB1 3EU, UK.

Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common- and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.
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http://dx.doi.org/10.1016/j.ajhg.2017.04.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473732PMC
June 2017

Shared genetic influences between dimensional ASD and ADHD symptoms during child and adolescent development.

Mol Autism 2017 4;8:18. Epub 2017 Apr 4.

MRC Integrative Epidemiology Unit (MRC IEU), University of Bristol, Bristol, UK.

Background: Shared genetic influences between attention-deficit/hyperactivity disorder (ADHD) symptoms and autism spectrum disorder (ASD) symptoms have been reported. Cross-trait genetic relationships are, however, subject to dynamic changes during development. We investigated the continuity of genetic overlap between ASD and ADHD symptoms in a general population sample during childhood and adolescence. We also studied uni- and cross-dimensional trait-disorder links with respect to genetic ADHD and ASD risk.

Methods: Social-communication difficulties ( ≤ 5551, Social and Communication Disorders Checklist, SCDC) and combined hyperactive-impulsive/inattentive ADHD symptoms ( ≤ 5678, Strengths and Difficulties Questionnaire, SDQ-ADHD) were repeatedly measured in a UK birth cohort (ALSPAC, age 7 to 17 years). Genome-wide summary statistics on clinical ASD (5305 cases; 5305 pseudo-controls) and ADHD (4163 cases; 12,040 controls/pseudo-controls) were available from the Psychiatric Genomics Consortium. Genetic trait variances and genetic overlap between phenotypes were estimated using genome-wide data.

Results: In the general population, genetic influences for SCDC and SDQ-ADHD scores were shared throughout development. Genetic correlations across traits reached a similar strength and magnitude (cross-trait  ≤ 1,    3 × 10) as those between repeated measures of the same trait (within-trait  ≤ 0.94,    7 × 10). Shared genetic influences between traits, especially during later adolescence, may implicate variants in K-RAS signalling upregulated genes (-meta = 6.4 × 10). Uni-dimensionally, each population-based trait mapped to the expected behavioural continuum: risk-increasing alleles for clinical ADHD were persistently associated with SDQ-ADHD scores throughout development (marginal regression  = 0.084%). An age-specific genetic overlap between clinical ASD and social-communication difficulties during childhood was also shown, as per previous reports. Cross-dimensionally, however, neither SCDC nor SDQ-ADHD scores were linked to genetic risk for disorder.

Conclusions: In the general population, genetic aetiologies between social-communication difficulties and ADHD symptoms are shared throughout child and adolescent development and may implicate similar biological pathways that co-vary during development. Within both the ASD and the ADHD dimension, population-based traits are also linked to clinical disorder, although much larger clinical discovery samples are required to reliably detect cross-dimensional trait-disorder relationships.
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http://dx.doi.org/10.1186/s13229-017-0131-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5379648PMC
March 2018

Genetic Overlap Between Schizophrenia and Developmental Psychopathology: Longitudinal and Multivariate Polygenic Risk Prediction of Common Psychiatric Traits During Development.

Schizophr Bull 2017 10;43(6):1197-1207

Biological Psychology, VU University, Amsterdam, The Netherlands.

Background: Several nonpsychotic psychiatric disorders in childhood and adolescence can precede the onset of schizophrenia, but the etiology of this relationship remains unclear. We investigated to what extent the association between schizophrenia and psychiatric disorders in childhood is explained by correlated genetic risk factors.

Methods: Polygenic risk scores (PRS), reflecting an individual's genetic risk for schizophrenia, were constructed for 2588 children from the Netherlands Twin Register (NTR) and 6127 from the Avon Longitudinal Study of Parents And Children (ALSPAC). The associations between schizophrenia PRS and measures of anxiety, depression, attention deficit hyperactivity disorder (ADHD), and oppositional defiant disorder/conduct disorder (ODD/CD) were estimated at age 7, 10, 12/13, and 15 years in the 2 cohorts. Results were then meta-analyzed, and a meta-regression analysis was performed to test differences in effects sizes over, age and disorders.

Results: Schizophrenia PRS were associated with childhood and adolescent psychopathology. Meta-regression analysis showed differences in the associations over disorders, with the strongest association with childhood and adolescent depression and a weaker association for ODD/CD at age 7. The associations increased with age and this increase was steepest for ADHD and ODD/CD. Genetic correlations varied between 0.10 and 0.25.

Conclusion: By optimally using longitudinal data across diagnoses in a multivariate meta-analysis this study sheds light on the development of childhood disorders into severe adult psychiatric disorders. The results are consistent with a common genetic etiology of schizophrenia and developmental psychopathology as well as with a stronger shared genetic etiology between schizophrenia and adolescent onset psychopathology.
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http://dx.doi.org/10.1093/schbul/sbx031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737694PMC
October 2017

LD Hub: a centralized database and web interface to perform LD score regression that maximizes the potential of summary level GWAS data for SNP heritability and genetic correlation analysis.

Bioinformatics 2017 01 22;33(2):272-279. Epub 2016 Sep 22.

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Motivation: LD score regression is a reliable and efficient method of using genome-wide association study (GWAS) summary-level results data to estimate the SNP heritability of complex traits and diseases, partition this heritability into functional categories, and estimate the genetic correlation between different phenotypes. Because the method relies on summary level results data, LD score regression is computationally tractable even for very large sample sizes. However, publicly available GWAS summary-level data are typically stored in different databases and have different formats, making it difficult to apply LD score regression to estimate genetic correlations across many different traits simultaneously.

Results: In this manuscript, we describe LD Hub - a centralized database of summary-level GWAS results for 173 diseases/traits from different publicly available resources/consortia and a web interface that automates the LD score regression analysis pipeline. To demonstrate functionality and validate our software, we replicated previously reported LD score regression analyses of 49 traits/diseases using LD Hub; and estimated SNP heritability and the genetic correlation across the different phenotypes. We also present new results obtained by uploading a recent atopic dermatitis GWAS meta-analysis to examine the genetic correlation between the condition and other potentially related traits. In response to the growing availability of publicly accessible GWAS summary-level results data, our database and the accompanying web interface will ensure maximal uptake of the LD score regression methodology, provide a useful database for the public dissemination of GWAS results, and provide a method for easily screening hundreds of traits for overlapping genetic aetiologies.

Availability And Implementation: The web interface and instructions for using LD Hub are available at http://ldsc.broadinstitute.org/ CONTACT: [email protected] information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btw613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542030PMC
January 2017
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