Genomic risk prediction of coronary artery disease in nearly 500,000 adults implications for early screening and primary prevention, bioRxiv, 2018-01-20
AbstractBackgroundCoronary artery disease (CAD) has substantial heritability and a polygenic architecture; however, genomic risk scores have not yet leveraged the totality of genetic information available nor been externally tested at population-scale to show potential utility in primary prevention.MethodsUsing a meta-analytic approach to combine large-scale genome-wide and targeted genetic association data, we developed a new genomic risk score for CAD (metaGRS), consisting of 1.7 million genetic variants. We externally tested metaGRS, individually and in combination with available conventional risk factors, in 22,242 CAD cases and 460,387 non-cases from UK Biobank.FindingsIn UK Biobank, a standard deviation increase in metaGRS had a hazard ratio (HR) of 1.71 (95% CI 1.68–1.73) for CAD, greater than any other externally tested genetic risk score. Individuals in the top 20% of the metaGRS distribution had a HR of 4.17 (95% CI 3.97–4.38) compared with those in the bottom 20%. The metaGRS had higher C-index (C=0.623, 95% CI 0.615–0.631) for incident CAD than any of four conventional factors (smoking, diabetes, hypertension, and body mass index), and addition of the metaGRS to a model of conventional risk factors increased C-index by 3.7%. In individuals on lipid-lowering or anti-hypertensive medications at recruitment, metaGRS hazard for incident CAD was significantly but only partially attenuated with HR of 2.83 (95% CI 2.61– 3.07) between the top and bottom 20% of the metaGRS distribution.InterpretationRecent genetic association studies have yielded enough information to meaningfully stratify individuals using the metaGRS for CAD risk in both early and later life, thus enabling targeted primary intervention in combination with conventional risk factors. The metaGRS effect was partially attenuated by lipid and blood pressure-lowering medication, however other prevention strategies will be required to fully benefit from earlier genomic risk stratification.FundingNational Health and Medical Research Council of Australia, British Heart Foundation, Australian Heart Foundation.
biorxiv genetics 100-200-users 2018Genome-wide association analysis of lifetime cannabis use (N=184,765) identifies new risk loci, genetic overlap with mental health, and a causal influence of schizophrenia on cannabis use, bioRxiv, 2018-01-09
Cannabis use is a heritable trait [1] that has been associated with adverse mental health outcomes. To identify risk variants and improve our knowledge of the genetic etiology of cannabis use, we performed the largest genome-wide association study (GWAS) meta-analysis for lifetime cannabis use (N=184,765) to date. We identified 4 independent loci containing genome-wide significant SNP associations. Gene-based tests revealed 29 genome-wide significant genes located in these 4 loci and 8 additional regions. All SNPs combined explained 10% of the variance in lifetime cannabis use. The most significantly associated gene, CADM2, has previously been associated with substance use and risk-taking phenotypes [2–4]. We used S-PrediXcan to explore gene expression levels and found 11 unique eGenes. LD-score regression uncovered genetic correlations with smoking, alcohol use and mental health outcomes, including schizophrenia and bipolar disorder. Mendelian randomisation analysis provided evidence for a causal positive influence of schizophrenia risk on lifetime cannabis use.
biorxiv genetics 200-500-users 2018Genome-wide association study of 1 million people identifies 111 loci for atrial fibrillation, bioRxiv, 2018-01-05
SummaryTo understand the genetic variation underlying atrial fibrillation (AF), the most common cardiac arrhythmia, we performed a genome-wide association study (GWAS) of > 1 million people, including 60,620 AF cases and 970,216 controls. We identified 163 independent risk variants at 111 loci and prioritized 165 candidate genes likely to be involved in AF. Many of the identified risk variants fall near genes where more deleterious mutations have been reported to cause serious heart defects in humans or mice (MYH6, NKX2-5, PITX2, TBC1D32, TBX5),1,2 or near genes important for striated muscle function and integrity (e.g. MYH7, PKP2, SSPN, SGCA). Experiments in rabbits with heart failure and left atrial dilation identified a heterogeneous distributed molecular switch from MYH6 to MYH7 in the left atrium, which resulted in contractile and functional heterogeneity and may predispose to initiation and maintenance of atrial arrhythmia.
biorxiv genetics 100-200-users 2018Defects in the neuroendocrine axis cause global development delay in a Drosophila model of NGLY1 Deficiency, bioRxiv, 2018-01-02
ABSTRACTN-glycanase 1 (NGLY1) Deficiency is a rare monogenic multi-system disorder first described in 2014. NGLY1 is evolutionarily conserved in model organisms, including the Drosophila melanogaster NGLY1 homolog, Pngl. Here we conducted a natural history study and chemical-modifier screen on a new fly model of NGLY1 Deficiency engineered with a nonsense mutation in Pngl at codon 420, resulting in truncation of the C-terminal carbohydrate-binding PAW domain. Homozygous mutant animals exhibit global development delay, pupal lethality and small body size as adults. We developed a 96-well-plate, image-based, quantitative assay of Drosophila larval size for use in a screen of the 2,650-member Microsource Spectrum compound library of FDA approved drugs, bioactive tool compounds, and natural products. We found that the cholesterol-derived ecdysteroid molting hormone 20-hydroxyecdysone (20E) rescued the global developmental delay in mutant homozygotes. Targeted expression of a human NGLY1 transgene to tissues involved in ecdysteroidogenesis, e.g., prothoracic gland, also rescues global developmental delay in mutant homozygotes. Finally, the proteasome inhibitor bortezomib is a potent enhancer of global developmental delay in our fly model, evidence of a defective proteasome “bounce-back” response that is also observed in nematode and cellular models of NGLY1 Deficiency. Together, these results demonstrate the therapeutic relevance of a new fly model of NGLY1 Deficiency for drug discovery, biomarker discovery, pharmacodynamics studies, and gene modifier screens.
biorxiv genetics 0-100-users 2018A genome-wide association study for shared risk across major psychiatric disorders in a nation-wide birth cohort implicates fetal neurodevelopment as a key mediator, bioRxiv, 2017-12-30
AbstractThere is mounting evidence that seemingly diverse psychiatric disorders share genetic etiology, but the biological substrates mediating this overlap are not well characterized. Here, we leverage the unique iPSYCH study, a nationally representative cohort ascertained through clinical psychiatric diagnoses indicated in Danish national health registers. We confirm previous reports of individual and cross-disorder SNP-heritability for major psychiatric disorders and perform a cross-disorder genome-wide association study. We identify four novel genome-wide significant loci encompassing variants predicted to regulate genes expressed in radial glia and interneurons in the developing neocortex during midgestation. This epoch is supported by partitioning cross-disorder SNP-heritability which is enriched at regulatory chromatin active during fetal neurodevelopment. These findings indicate that dysregulation of genes that direct neurodevelopment by common genetic variants results in general liability for many later psychiatric outcomes.
biorxiv genetics 0-100-users 2017Examining the genetic influences of educational attainment and the validity of value-added measures of progress, bioRxiv, 2017-12-15
AbstractIn this study, we estimate (i) the SNP heritability of educational attainment at three time points throughout the compulsory educational lifecourse; (ii) the SNP heritability of value-added measures of educational progress built from test data; and (iii) the extent to which value-added measures built from teacher rated ability may be biased due to measurement error. We utilise a genome wide approach using generalized restricted maximum likelihood (GCTA-GREML) to determine the total phenotypic variance in educational attainment and value-added measures that is attributable to common genetic variation across the genome within a sample of unrelated individuals from a UK birth cohort, the Avon Longitudinal Study of Parents and Children. Our findings suggest that the heritability of educational attainment measured using point score test data increases with age from 47% at age 11 to 61% at age 16. We also find that genetic variation does not contribute towards value-added measures created only from educational attainment point score data, but it does contribute a small amount to measures that additionally control for background characteristics (up to 20.09% [95%CI 6.06 to 35.71] from age 11 to 14). Finally, our results show that value-added measures built from teacher rated ability have higher heritability than those built from exam scores. Our findings suggest that the heritability of educational attainment increases through childhood and adolescence. Value-added measures based upon fine grain point scores may be less prone to between-individual genomic differences than measures that control for students’ backgrounds, or those built from more subjective measures such as teacher rated ability.
biorxiv genetics 0-100-users 2017