ORCID Profile
0000-0001-6423-105X
Current Organisation
University of Oxford
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Publisher: Research Square Platform LLC
Date: 04-01-2022
DOI: 10.21203/RS.3.RS-1175817/V1
Abstract: Previous genome-wide association studies (GWAS) of stroke, the second leading cause of death, have been conducted in populations of predominantly European ancestry.1,2 We undertook cross-ancestry GWAS meta-analyses of stroke and its subtypes in 110,182 stroke patients (33% non-European) and 1,503,898 control in iduals of five ancestries from population- and clinic-based studies, nearly doubling the number of cases in previous stroke GWAS. We identified association signals at 89 independent loci, of which 61 were novel. Effect sizes were overall highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis using a novel machine-learning approach,3 transcriptome and proteome-wide association analyses revealed putative causal genes (e.g. SH3PXD2A and FURIN) and variants (e.g. at GRK5 and NOS3). Using a novel three-pronged approach,4 we provided genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWAS with vascular risk factor GWAS (iPGS) showed strong prediction of ischemic stroke risk in European and, for the first time, East-Asian populations.5,6 The iPGS performed better than stroke PGS alone and better than previous best iPGS, in Europeans and East-Asians. Transferability of European-specific iPGS to East-Asians was limited. Stroke genetic risk scores were predictive of ischemic stroke independent of clinical risk factors in 52,600 clinical trial participants with cardiometabolic disease and performed considerably better than previous scores, both in Europeans and East-Asians. Altogether our results provide critical insight to inform biology, reveal potential drug targets for intervention, and provide genetic risk prediction tools across ancestries for targeted prevention.
Publisher: Springer Science and Business Media LLC
Date: 22-12-2020
Publisher: Springer Science and Business Media LLC
Date: 03-2023
DOI: 10.1038/S41588-023-01314-0
Abstract: Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. In idual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.
Publisher: Springer Science and Business Media LLC
Date: 05-2022
DOI: 10.1038/S41588-022-01062-7
Abstract: Estimates from genome-wide association studies (GWAS) of unrelated in iduals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For ex le, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for ex le, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.
Publisher: Springer Science and Business Media LLC
Date: 25-09-2023
Publisher: Springer Science and Business Media LLC
Date: 30-09-2022
DOI: 10.1038/S41586-022-05165-3
Abstract: Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry 1,2 . Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control in iduals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control in iduals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated ( P 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis 3 , and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN ) and variants (such as at GRK5 and NOS3 ). Using a three-pronged approach 4 , we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry 5 . Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
Publisher: American Medical Association (AMA)
Date: 11-11-2009
Publisher: Springer Science and Business Media LLC
Date: 14-11-2022
Publisher: Springer Science and Business Media LLC
Date: 31-10-2019
DOI: 10.1038/S41467-019-12283-6
Abstract: In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients ( F ROH ) for .4 million in iduals, we show that F ROH is significantly associated ( p 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of F ROH are confirmed within full-sibling pairs, where the variation in F ROH is independent of all environmental confounding.
Publisher: MDPI AG
Date: 15-07-2015
DOI: 10.3390/NU7075253
Abstract: Limited evidence exists for the association between diet pattern and obesity phenotypes among Chinese adults. In the present study, we analyzed the cross-sectional data from 474,192 adults aged 30–79 years from the China Kadoorie Biobank baseline survey. Food consumption was collected by an interviewer-administered questionnaire. Three dietary patterns were extracted by factor analysis combined with cluster analysis. After being adjusted for potential confounders, in iduals following a traditional southern dietary pattern had the lowest body mass index (BMI) and waist circumference (WC) the Western/new affluence dietary pattern had the highest BMI and the traditional northern dietary pattern had the highest WC. Compared to the traditional southern dietary pattern in multivariable adjusted logistic models, in iduals following a Western/new affluence dietary pattern had a significantly increased risk of general obesity (prevalence ratio (PR): 1.06, 95% confidence interval (CI): 1.03–1.08) and central obesity (PR: 1.07, 95% CI: 1.06–1.08). The corresponding risks for the traditional northern dietary pattern were 1.05 (1.02–1.09) and 1.17 (1.25–1.18), respectively. In addition, the associations were modified by lifestyle behaviors, and the combined effects with alcohol drinking, tobacco smoking, and physical activity were analyzed. Further prospective studies are needed to elucidate the diet-obesity relationships.
Publisher: Springer Science and Business Media LLC
Date: 16-11-2020
Publisher: Research Square Platform LLC
Date: 29-07-2022
DOI: 10.21203/RS.3.RS-1832470/V1
Abstract: Genome-wide association studies (GWAS) in predominately European-ancestry (EUR) populations have identified numerous genetic variants associated with adiposity-related traits. An emerging challenge is the limited transferability of genetic scores constructed based on GWAS results from one ancestry for trait prediction in other ancestries. We performed trans-ancestry meta-analysis (TAMA) for eight adiposity-related traits using genetic data from 96,124 East Asian (EAS) and 443,359 EUR in iduals. We identified genomic regions significantly associated with one or more traits. Despite EAS comprising only ~20% of the study population, genetic scores constructed from the trans-ancestry (TA) results accounted for between 30% and 79% more variation in the adiposity traits in EAS compared with scores derived from the EUR GWAS alone. Furthermore, TA scores also modestly improved variance explained in African/African American, Hispanic and South Asian populations. Our findings highlight the utility of TAMA for increasing variance explained by genetic scores across populations of different ancestries.
Publisher: American Medical Association (AMA)
Date: 22-07-2009
Publisher: Springer Science and Business Media LLC
Date: 25-11-2020
DOI: 10.1038/S41467-020-19742-5
Abstract: Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10 −8 , odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10 −8 , OR = 1.7 rs143445068, MAF = 0.8%, P = 5.2 × 10 −9 , OR = 3.4 rs183453668, MAF = 0.5%, P = 2.8 × 10 −8 , OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Zhengming Chen.