ORCID Profile
0000-0003-3073-717X
Current Organisation
Wellcome Sanger Institute
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Publisher: Public Library of Science (PLoS)
Date: 19-05-2022
DOI: 10.1371/JOURNAL.PMED.1003981
Abstract: Type 2 diabetes (T2D) is highly prevalent in British South Asians, yet they are underrepresented in research. Genes & Health (G& H) is a large, population study of British Pakistanis and Bangladeshis (BPB) comprising genomic and routine health data. We assessed the extent to which genetic risk for T2D is shared between BPB and European populations (EUR). We then investigated whether the integration of a polygenic risk score (PRS) for T2D with an existing risk tool (QDiabetes) could improve prediction of incident disease and the characterisation of disease subtypes. In this observational cohort study, we assessed whether common genetic loci associated with T2D in EUR in iduals were replicated in 22,490 BPB in iduals in G& H. We replicated fewer loci in G& H ( n = 76/338, 22%) than would be expected given power if all EUR-ascertained loci were transferable ( n = 101, 30% p = 0.001). Of the 27 transferable loci that were powered to interrogate this, only 9 showed evidence of shared causal variants. We constructed a T2D PRS and combined it with a clinical risk instrument (QDiabetes) in a novel, integrated risk tool (IRT) to assess risk of incident diabetes. To assess model performance, we compared categorical net reclassification index (NRI) versus QDiabetes alone. In 13,648 patients free from T2D followed up for 10 years, NRI was 3.2% for IRT versus QDiabetes (95% confidence interval (CI): 2.0% to 4.4%). IRT performed best in reclassification of in iduals aged less than 40 years deemed low risk by QDiabetes alone (NRI 5.6%, 95% CI 3.6% to 7.6%), who tended to be free from comorbidities and slim. After adjustment for QDiabetes score, PRS was independently associated with progression to T2D after gestational diabetes (hazard ratio (HR) per SD of PRS 1.23, 95% CI 1.05 to 1.42, p = 0.028). Using cluster analysis of clinical features at diabetes diagnosis, we replicated previously reported disease subgroups, including Mild Age-Related, Mild Obesity-related, and Insulin-Resistant Diabetes, and showed that PRS distribution differs between subgroups ( p = 0.002). Integrating PRS in this cluster analysis revealed a Probable Severe Insulin Deficient Diabetes (pSIDD) subgroup, despite the absence of clinical measures of insulin secretion or resistance. We also observed differences in rates of progression to micro- and macrovascular complications between subgroups after adjustment for confounders. Study limitations include the absence of an external replication cohort and the potential biases arising from missing or incorrect routine health data. Our analysis of the transferability of T2D loci between EUR and BPB indicates the need for larger, multiancestry studies to better characterise the genetic contribution to disease and its varied aetiology. We show that a T2D PRS optimised for this high-risk BPB population has potential clinical application in BPB, improving the identification of T2D risk (especially in the young) on top of an established clinical risk algorithm and aiding identification of subgroups at diagnosis, which may help future efforts to stratify care and treatment of the disease.
Publisher: Springer Science and Business Media LLC
Date: 26-08-2021
Publisher: Cold Spring Harbor Laboratory
Date: 25-10-2017
DOI: 10.1101/209171
Abstract: Investigation of the genetic architecture of gene expression traits has aided interpretation of disease and trait-associated genetic variants, however key aspects of expression quantitative trait (eQTL) study design and analysis remain understudied. We used extensive, empirically-driven simulations to explore eQTL study design and the performance of various analysis strategies. Across multiple testing correction methods, false discoveries of genes with eQTLs (eGenes) were substantially inflated when false discovery rate (FDR) control was applied to all tests, and only appropriately controlled using hierarchical procedures. All multiple testing correction procedures had low power and inflated FDR for eGenes whose causal SNPs had small allele frequencies using small s le sizes (e.g. frequency % in 100 s les), indicating that even moderately low frequency eQTL SNPs (eSNPs) in these studies are enriched for false discoveries. In scenarios with ≥80% power, the top eSNP was the true simulated eSNP 90% of the time, but substantially less frequently for very common eSNPs (minor allele frequencies %). Overestimation of eQTL effect sizes, so-called “Winner’s Curse”, was common in low and moderate power settings. To address this, we developed a bootstrap method (BootstrapQTL) which led to more accurate effect size estimation. These insights provide a foundation for future eQTL studies, especially those with s ling constraints and subtly different conditions.
Publisher: Public Library of Science (PLoS)
Date: 22-06-2017
Publisher: Cold Spring Harbor Laboratory
Date: 03-09-2020
DOI: 10.1101/2020.09.02.279190
Abstract: Previous genetic and public health research in the Pakistani population has focused on the role of consanguinity in increasing recessive disease risk, but little is known about its recent population history or the effects of endogamy. Here, we investigate fine-scale population structure, history and consanguinity patterns using genetic and questionnaire data from ,000 British Pakistani in iduals, mostly with roots in Azad Kashmir and Punjab. We reveal strong recent population structure driven by the biraderi social stratification system. We find that all subgroups have had low effective population sizes (N e ) over the last 50 generations, with some showing a decrease in N e 15-20 generations ago that has resulted in extensive identity-by-descent sharing and increased homozygosity. Using new theory, we show that the footprint of regions of homozygosity in the two largest subgroups is about twice that expected naively based on the self-reported consanguinity rates and the inferred historical N e trajectory. These results demonstrate the impact of the cultural practices of endogamy and consanguinity on population structure and genomic ersity in British Pakistanis, and have important implications for medical genetic studies.
Publisher: Springer Science and Business Media LLC
Date: 28-07-2020
DOI: 10.1038/S41467-020-17477-X
Abstract: Chronic immune-mediated diseases of adulthood often originate in early childhood. To investigate genetic associations between neonatal immunity and disease, we map expression quantitative trait loci (eQTLs) in resting myeloid cells and CD4 + T cells from cord blood s les, as well as in response to lipopolysaccharide (LPS) or phytohemagglutinin (PHA) stimulation, respectively. Cis -eQTLs are largely specific to cell type or stimulation, and 31% and 52% of genes with cis -eQTLs have response eQTLs (reQTLs) in myeloid cells and T cells, respectively. We identified cis regulatory factors acting as mediators of trans effects. There is extensive colocalisation between condition-specific neonatal cis -eQTLs and variants associated with immune-mediated diseases, in particular CTSH had widespread colocalisation across diseases. Mendelian randomisation shows causal neonatal gene expression effects on disease risk for BTN3A2 , HLA-C and others. Our study elucidates the genetics of gene expression in neonatal immune cells, and aetiological origins of autoimmune and allergic diseases.
Publisher: The Endocrine Society
Date: 20-06-2023
Abstract: The melanocortin 3 receptor (MC3R) has recently emerged as a critical regulator of pubertal timing, linear growth, and the acquisition of lean mass in humans and mice. In population-based studies, heterozygous carriers of deleterious variants in MC3R report a later onset of puberty than noncarriers. However, the frequency of such variants in patients who present with clinical disorders of pubertal development is currently unknown. This work aimed to determine whether deleterious MC3R variants are more frequently found in patients clinically presenting with constitutional delay of growth and puberty (CDGP) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH). We examined the sequence of MC3R in 362 adolescents with a clinical diagnosis of CDGP and 657 patients with nIHH, experimentally characterized the signaling properties of all nonsynonymous variants found and compared their frequency to that in 5774 controls from a population-based cohort. Additionally, we established the relative frequency of predicted deleterious variants in in iduals with self-reported delayed vs normally timed menarche/voice-breaking in the UK Biobank cohort. MC3R loss-of-function variants were infrequent but overrepresented in patients with CDGP (8/362 [2.2%] OR = 4.17 P = .001). There was no strong evidence of overrepresentation in patients with nIHH (4/657 [0.6%] OR = 1.15 P = .779). In 246 328 women from the UK Biobank, predicted deleterious variants were more frequently found in those self-reporting delayed (aged ≥16 years) vs normal age at menarche (OR = 1.66 P = 3.90E-07). We have found evidence that functionally damaging variants in MC3R are overrepresented in in iduals with CDGP but are not a common cause of this phenotype.
Publisher: Springer Science and Business Media LLC
Date: 17-08-2023
Publisher: Elsevier BV
Date: 09-2020
Publisher: Cold Spring Harbor Laboratory
Date: 27-06-2019
DOI: 10.1101/683086
Abstract: Chronic immune-mediated diseases of adulthood often originate in early childhood. To investigate genetic associations between neonatal immunity and disease, we collected cord blood s les from a birth cohort and mapped expression quantitative trait loci (eQTLs) in resting monocytes and CD4 + T cells as well as in response to lipopolysaccharide (LPS) or phytohemagglutinin (PHA) stimulation, respectively. Cis -eQTLs were largely specific to cell type or stimulation, and response eQTLs were identified for 31% of genes with cis -eQTLs (eGenes) in monocytes and 52% of eGenes in CD4 + T cells. We identified trans -eQTLs and mapped cis regulatory factors which act as mediators of trans effects. There was extensive colocalisation of causal variants for cell type- and stimulation-specific neonatal cis -eQTLs and those of autoimmune and allergic diseases, in particular CTSH (Cathepsin H) which showed widespread colocalisation across diseases. Mendelian randomisation showed causal neonatal gene transcription effects on disease risk for BTN3A2 , HLA-C and many other genes. Our study elucidates the genetics of gene expression in neonatal conditions and cell types as well as the aetiological origins of autoimmune and allergic diseases.
Publisher: Cold Spring Harbor Laboratory
Date: 16-07-2021
DOI: 10.1101/2021.07.12.21259837
Abstract: Type 2 diabetes is highly prevalent in British Pakistanis and Bangladeshis (BPB). The Genes & Health (G& H) cohort offers means to explore genetic determinants of disease in BPBs. We assessed whether common genetic loci associated with type 2 diabetes in European-ancestry in iduals (EUR) replicate in G& H. We constructed a type 2 diabetes polygenic risk score (PRS) and combined it with a clinical risk instrument (QDiabetes) to build a novel, integrated risk tool (IRT). We compared IRT performance using net reclassification index (NRI) versus QDiabetes alone.We compared PRS distribution between type 2 diabetes subgroups identified by clinical features at diagnosis. We replicated fewer loci in G& H (n = 76/338, 22%) than would be expected given power if all EUR-ascertained loci were transferable (n = 95, 28%) (p-value = 0.01). In 13,648 patients free from type 2 diabetes followed up for 10 years, NRI was 3.2% for IRT versus QDiabetes (95% confidence interval 2.0 - 4.4%). IRT performed best in reclassification of young adults deemed low risk by QDiabetes as high risk. PRS was independently associated with progression to type 2 diabetes after gestational diabetes (p = 0.028). Mean type 2 diabetes PRS differed between phenotypically-defined type 2 diabetes subgroups (p = 0.002). The type 2 diabetes PRS has broad potential clinical application in BPB, improving identification of type 2 diabetes risk (especially in the young), and characterisation of subgroups at diagnosis. Wellcome Trust, MRC, NIHR, and others. People of south Asian origin are disproportionately affected by type 2 diabetes, yet are underrepresented in genetic studies assessing its causation. To date, there have been no published studies that systematically assess how type 2 diabetes genetic risk loci identified in European in iduals can be transferred into south Asians, taking into account power and differences in linkage disequilibrium, nor has the clinical utility of a type 2 diabetes polygenic risk score (PRS) been evaluated in this ethnic group. For coronary artery disease, integration of PRS with clinical risk tools has been shown to enhance the prediction of incident disease, in multiple ancestral groups. For type 2 diabetes, whilst it is known from multiple studies of Europeans that PRS can enhance prediction of incident disease, no study has examined PRS performance when integrated with an existing clinical risk tool, although it has potentially significant clinical impact. The identification of type 2 diabetes subgroups at disease presentation has now been studied extensively, but the influence of polygenic risk in characterising these subgroups has not been tested. We examined prior evidence using multiple updated searches across MEDLINE, CINAHL, EMBASE, MEDRXIV and BIORXIV on 29/6/2021 with terms including “type 2 diabetes” and “polygenic risk scor$,” “genetic risk scor$”, “subgroup”, and “cluster” did not identify similar published work. In the first study to systematically assess the transferability of genetic loci associated with type 2 diabetes in European ancestry in iduals into a British Pakistanis and Bangladeshis (BPBs), we find fewer transferable loci than would be expected, accounting for power. We also construct a type 2 diabetes PRS for BPBs and show that its integration with QDiabetes enhances 10-year prediction of incident type 2 diabetes, especially in in iduals aged less than 40 years deemed low risk by QDiabetes alone, who tended to be free from comorbidities, and relatively slim. Additionally, we find the PRS is independently associated with progression from gestational diabetes mellitus to type 2 diabetes in BPBs, replicating previous findings in European in iduals. We replicate previously-reported subgroups of type 2 diabetes in BPBs, including Mild Age-Related Diabetes, Mild Obesity-Related Diabetes, and Insulin-Resistant Diabetes, and show that PRS distribution differs between clinically-defined clusters. In a novel clustering approach integrating PRS with clinical features, we identify a previously unreported subgroup we name “Clinically Undifferentiated High Polygenic Susceptibility Diabetes”, and observe differences in rates of progression to micro- and macrovascular complications between subgroups. A single, low-cost genotyping array can now determine the polygenic risk of multiple diseases in parallel at any point in the life course. We build on existing genomic resources to build a type 2 diabetes PRS that can be used to predict incident disease in a specific ancestral group that is disproportionately affected by the condition. We show that a PRS, when integrated with an established and well-validated clinical risk algorithm, has significant potential clinical utility as both a means to better estimate in idual disease risk, and to elucidate the influence of genetics on disease subgroups to aid future efforts to stratify care and treatment of the disease.
Publisher: Springer Science and Business Media LLC
Date: 10-12-2021
DOI: 10.1038/S41467-021-27394-2
Abstract: Previous genetic and public health research in the Pakistani population has focused on the role of consanguinity in increasing recessive disease risk, but little is known about its recent population history or the effects of endogamy. Here, we investigate fine-scale population structure, history and consanguinity patterns using genotype chip data from 2,200 British Pakistanis. We reveal strong recent population structure driven by the biraderi social stratification system. We find that all subgroups have had low recent effective population sizes (N e ), with some showing a decrease 15‒20 generations ago that has resulted in extensive identity-by-descent sharing and homozygosity, increasing the risk of recessive disorders. Our results from two orthogonal methods (one using machine learning and the other coalescent-based) suggest that the detailed reporting of parental relatedness for mothers in the cohort under-represents the true levels of consanguinity. These results demonstrate the impact of cultural practices on population structure and genomic ersity in Pakistanis, and have important implications for medical genetic studies.
Publisher: Springer Science and Business Media LLC
Date: 09-08-2022
DOI: 10.1038/S41467-022-32095-5
Abstract: In iduals with South Asian ancestry have a higher risk of heart disease than other groups but have been largely excluded from genetic research. Using data from 22,000 British Pakistani and Bangladeshi in iduals with linked electronic health records from the Genes & Health cohort, we conducted genome-wide association studies of coronary artery disease and its key risk factors. Using power-adjusted transferability ratios, we found evidence for transferability for the majority of cardiometabolic loci powered to replicate. The performance of polygenic scores was high for lipids and blood pressure, but lower for BMI and coronary artery disease. Adding a polygenic score for coronary artery disease to clinical risk factors showed significant improvement in reclassification. In Mendelian randomisation using transferable loci as instruments, our findings were consistent with results in European-ancestry in iduals. Taken together, trait-specific transferability of trait loci between populations is an important consideration with implications for risk prediction and causal inference.
Publisher: Elsevier BV
Date: 12-2019
Publisher: eLife Sciences Publications, Ltd
Date: 24-03-2020
DOI: 10.7554/ELIFE.54363
Abstract: By sequencing autozygous human populations, we identified a healthy adult woman with lifelong complete knockout of HAO1 (expected ~1 in 30 million outbred people). HAO1 (glycolate oxidase) silencing is the mechanism of lumasiran, an investigational RNA interference therapeutic for primary hyperoxaluria type 1. Her plasma glycolate levels were 12 times, and urinary glycolate 6 times, the upper limit of normal observed in healthy reference in iduals (n = 67). Plasma metabolomics and lipidomics (1871 biochemicals) revealed 18 markedly elevated biochemicals ( sd outliers versus n = 25 controls) suggesting additional HAO1 effects. Comparison with lumasiran preclinical and clinical trial data suggested she has % residual glycolate oxidase activity. Cell line p.Leu333SerfsTer4 expression showed markedly reduced HAO1 protein levels and cellular protein mis-localisation. In this woman, lifelong HAO1 knockout is safe and without clinical phenotype, de-risking a therapeutic approach and informing therapeutic mechanisms. Unlocking evidence from the ersity of human genetic variation can facilitate drug development.
Publisher: Cold Spring Harbor Laboratory
Date: 08-09-2022
DOI: 10.1101/2022.09.08.507084
Abstract: Our understanding of the genetic architecture of the human cerebral cortex is limited both in terms of the ersity of brain structural phenotypes and the anatomical granularity of their associations with genetic variants. Here, we conducted genome-wide association meta-analysis of 13 structural and diffusion magnetic resonance imaging derived cortical phenotypes, measured globally and at 180 bilaterally averaged regions in 36,843 in iduals from the UK Biobank and the ABCD cohorts. These phenotypes include cortical thickness, surface area, grey matter volume, and measures of folding, neurite density, and water diffusion. We identified 4,349 experiment-wide significant loci associated with global and regional phenotypes. Multiple lines of analyses identified four genetic latent structures and causal relationships between surface area and some measures of cortical folding. These latent structures partly relate to different underlying gene expression trajectories during development and are enriched for different cell types. We also identified differential enrichment for neurodevelopmental and constrained genes and demonstrate that common genetic variants associated with surface area and volume specifically are associated with cephalic disorders. Finally, we identified complex inter-phenotype and inter-regional genetic relationships among the 13 phenotypes which reflect developmental differences among them. These analyses help refine the role of common genetic variants in human cortical development and organisation. GWAS of 2,347 neuroimaging phenotypes shed light on the global and regional genetic organisation of the cortex, underlying cellular and developmental processes, and links to neurodevelopmental and cephalic disorders.
Publisher: Cold Spring Harbor Laboratory
Date: 24-06-2021
DOI: 10.1101/2021.06.22.21259323
Abstract: In iduals with South Asian ancestry have higher risk of heart disease than other groups in Western countries however, most genetic research has focused on European-ancestry (EUR) in iduals. It is unknown whether reported genetic loci and polygenic scores (PGSs) for cardiometabolic traits are transferable to South Asians, and whether PGSs have utility in clinical settings. Using data from 22,000 British Pakistani and Bangladeshi in iduals with linked electronic health records from the Genes & Health cohort (G& H), we conducted genome-wide association studies (GWAS) and characterised the genetic architecture of coronary artery disease (CAD), body mass index (BMI), lipid biomarkers and blood pressure. We applied a new technique to assess the extent to which loci from GWAS in EUR s les were transferable. We tested how well existing findings from EUR studies performed in genetic risk prediction and Mendelian randomisation in G& H. Trans-ancestry genetic correlations between G& H and EUR s les for the tested traits were not significantly lower than 1, except for BMI (r g =0.85, p=0.02). We found evidence for transferability for the vast majority of loci from EUR discovery studies that were sufficiently powered to replicate in G& H. PGSs showed variable transferability in G& H, with the relative accuracy compared to EUR (ratio of incremental r 2 /AUC) ≥0.95 for HDL-C, triglycerides, and blood pressure, but lower for BMI (0.78) and CAD (0.42). We observed significant improvement in categorical net reclassification in G& H (NRI=3.9% 95% CI 0.9–7.0) when adding a previously developed CAD PGS to clinical risk factors (QRISK3). We used transferable loci as genetic instruments in trans-ancestry Mendelian randomisation and found evidence of an increased CAD risk for higher LDL-C and BMI, and for lower HDL-C in G& H, consistent with our findings for EUR s les. The genetic loci for CAD and its risk factors are largely transferable from EUR studies to British Pakistanis and Bangladeshis, whereas the transferability of PGSs varies greatly between traits. Our analyses suggest clinical utility for addition of PGS to existing clinical risk prediction tools for this population. This is the first study to explore the transferability of GWAS findings and PGSs for CAD and related cardiometabolic traits in British Pakistani and Bangladeshi in iduals from a cohort with real-world electronic clinical data. We propose a new approach to assessing transferability of GWAS loci between populations, which can serve as a new methodological standard in this developing field. We find evidence of overall high transferability of GWAS loci in British Pakistanis and Bangladeshis. BMI, lipids and blood pressure show the highest transferability of loci, and CAD the lowest. The transferability of PGSs varied between traits, being high for HDL-C, triglycerides and blood pressure but more modest for CAD, BMI and LDL-C. Our results suggest that, for some traits, the use of transferable GWAS loci improves the robustness of Mendelian randomisation estimates in non-Europeans. The polygenic score for CAD derived from genetic studies of European in iduals improves reclassification on top of clinical risk factors in British Pakistanis and Bangladeshis. The improvement was driven by identification of more cases in younger in iduals (25–54 years old), and of controls in older in iduals (55–84 years old). Incorporation of the polygenic score for CAD into risk prediction models is likely to prevent cardiovascular events and deaths in this population.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Qin Qin Huang.