Biology subjects

Cook, J. P.

Publications and source records attributed to Cook, J. P..

4 recordsLinked to original sources

bioRxiv2018

Trans-ethnic genome-wide association study provides insight into effector genes and molecular mechanisms for kidney function and highlights a causal effect on kidney-specific disease aetiologies

Chronic kidney disease (CKD) affects [~]10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assembled genome-wide association studies (GWAS)1-3 of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals from four ancestry groups. We identified 93 loci (20 novel), which were delineated to 127 distinct association signals. These signals were homogenous across ancestries, and were enriched for protein-coding exons, kidney-specific histone modifications, and transcription factor binding sites for HDAC2 and EZH2. Fine-mapping revealed 40 high-confidence variants driving eGFR associations and highlighted potential causal genes with cell-type specific expression in glomerulus, and proximal and distal nephron. Mendelian randomisation (MR) supported causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure (DBP) and hypertension. These results define novel molecular mechanisms and effector genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.

genetics↗

bioRxiv2018

New genetic signals for lung function highlight pathways and pleiotropy, and chronic obstructive pulmonary disease associations across multiple ancestries

Reduced lung function predicts mortality and is key to the diagnosis of COPD. In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, one-half of which are new. In combination these variants strongly predict COPD in deeply-phenotyped patient populations. Furthermore, the combined effect of these variants showed generalisability across smokers and never-smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.

genomics↗

bioRxiv2018

Genome-wide association analysis identifies 27 novel loci associated with uterine leiomyomata revealing common genetic origins with endometriosis

Uterine leiomyomata (UL), also known as uterine fibroids, are the most common neoplasms of the reproductive tract and the primary cause for hysterectomy, leading to considerable impact on womens lives as well as high economic burden1,2. Genetic epidemiologic studies indicate that heritable risk factors contribute to UL pathogenesis3. Previous genome-wide association studies (GWAS) identified five loci associated with UL at genome-wide significance (P < 5 x 10-8)4-6. We conducted GWAS meta-analysis in 20,406 cases and 223,918 female controls of white European ancestry, identifying 24 genome-wide significant independent loci; 17 replicated in an unrelated cohort of 15,068 additional cases and 43,587 female controls. Aggregation of discovery and replication studies (35,474 cases and 267,505 female controls) revealed six additional significant loci. Interestingly, four of the 17 loci identified and replicated in these analyses have also been associated with risk for endometriosis - another common gynecologic disorder. These findings increase our understanding of the biological mechanisms underlying UL development, and suggest overlapping genetic origins with endometriosis.

genomics↗

bioRxiv2018

Fine-mapping of an expanded set of type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps

We aggregated genome-wide genotyping data from 32 European-descent GWAS (74,124 T2D cases, 824,006 controls) imputed to high-density reference panels of >30,000 sequenced haplotypes. Analysis of {small tilde}27M variants ({small tilde}21M with minor allele frequency [MAF]<5%), identified 243 genome-wide significant loci (p<5x10-8; MAF 0.02%-50%; odds ratio [OR] 1.04-8.05), 135 not previously-implicated in T2D-predisposition. Conditional analyses revealed 160 additional distinct association signals (p<10-5) within the identified loci. The combined set of 403 T2D-risk signals includes 56 low-frequency (0.5%[≤]MAF<5%) and 24 rare (MAF<0.5%) index SNPs at 60 loci, including 14 with estimated allelic OR>2. Forty-one of the signals displayed effect-size heterogeneity between BMI-unadjusted and adjusted analyses. Increased sample size and improved imputation led to substantially more precise localisation of causal variants than previously attained: at 51 signals, the lead variant after fine-mapping accounted for >80% posterior probability of association (PPA) and at 18 of these, PPA exceeded 99%. Integration with islet regulatory annotations enriched for T2D association further reduced median credible set size (from 42 variants to 32) and extended the number of index variants with PPA>80% to 73. Although most signals mapped to regulatory sequence, we identified 18 genes as human validated therapeutic targets through coding variants that are causal for disease. Genome wide chip heritability accounted for 18% of T2D-risk, and individuals in the 2.5% extremes of a polygenic risk score generated from the GWAS data differed >9-fold in risk. Our observations highlight how increases in sample size and variant diversity deliver enhanced discovery and single-variant resolution of causal T2D-risk alleles, and the consequent impact on mechanistic insights and clinical translation.

genomics↗