ORCID Profile
0000-0002-4454-9084
Current Organisations
Wellcome Sanger Institute
,
University of Cambridge Saint John's College
,
Wellcome Trust Sanger Institute
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Publisher: Springer Science and Business Media LLC
Date: 02-06-2022
DOI: 10.1038/S41588-022-01072-5
Abstract: The substantial phenotypic heterogeneity in autism limits our understanding of its genetic etiology. To address this gap, here we investigated genetic differences between autistic in iduals ( n max = 12,893) based on core and associated features of autism, co-occurring developmental disabilities and sex. We conducted a comprehensive factor analysis of core autism features in autistic in iduals and identified six factors. Common genetic variants were associated with the core factors, but de novo variants were not. We found that higher autism polygenic scores (PGS) were associated with lower likelihood of co-occurring developmental disabilities in autistic in iduals. Furthermore, in autistic in iduals without co-occurring intellectual disability (ID), autism PGS are overinherited by autistic females compared to males. Finally, we observed higher SNP heritability for autistic males and for autistic in iduals without ID. Deeper phenotypic characterization will be critical in determining how the complex underlying genetics shape cognition, behavior and co-occurring conditions in autism.
Publisher: Cold Spring Harbor Laboratory
Date: 29-12-2021
DOI: 10.1101/2021.12.28.21267792
Abstract: The majority of clinical genetic testing focuses almost exclusively on regions of the genome that directly encode proteins. The important role of variants in non-coding regions in penetrant disease is, however, increasingly being demonstrated, and the use of whole genome sequencing in clinical diagnostic settings is rising across a large range of genetic disorders. Despite this, there is no existing guidance on how current guidelines designed primarily for variants in protein-coding regions should be adapted for variants identified in other genomic contexts. We convened a panel of clinical and research scientists with wide-ranging expertise in clinical variant interpretation, with specific experience in variants within non-coding regions. This panel discussed and refined an initial draft of the guidelines which were then extensively tested and reviewed by external groups. We discuss considerations specifically for variants in non-coding regions of the genome. We outline how to define candidate regulatory elements, highlight ex les of mechanisms through which non-coding region variants can lead to penetrant monogenic disease, and outline how existing guidelines can be adapted for these variants. These recommendations aim to increase the number and range of non-coding region variants that can be clinically interpreted, which, together with a compatible phenotype, can lead to new diagnoses and catalyse the discovery of novel disease mechanisms.
Publisher: Springer Science and Business Media LLC
Date: 03-11-2021
Publisher: Research Square Platform LLC
Date: 19-10-2023
Publisher: American Association for the Advancement of Science (AAAS)
Date: 07-12-2018
Abstract: The genetics of developmental disorders (DDs) is complex. Martin et al. wanted to determine the degree of recessive inheritance of DDs in protein-coding genes. They examined the exomes of more than 6000 families in populations with high and low proportions of consanguineous marriages. They found that 3.6% of DDs in in iduals of European ancestry involved recessive coding disorders, less than a tenth of the levels previously estimated. Furthermore, among South Asians with high parental relatedness, rather than most of the disorders arising from inherited variants, fewer than half had a recessive coding diagnosis. Science , this issue p. 1161
Publisher: Cold Spring Harbor Laboratory
Date: 24-07-2023
DOI: 10.1101/2023.07.24.23293070
Abstract: Autosomal recessive (AR) coding variants are a well-known cause of rare disorders. We quantified the contribution of these variants to developmental disorders (DDs) in the largest and most ancestrally erse s le to date, comprising 29,745 trios from the Deciphering Developmental Disorders (DDD) study and the genetic diagnostics company GeneDx, of whom 20.4% have genetically-inferred non-European ancestries. The estimated fraction of patients attributable to exome-wide AR coding variants ranged from ∼2% to ∼18% across genetically-inferred ancestry groups, and was significantly correlated with the average autozygosity (r=0.99, p=5x10 -6 ). Established AR DD-associated (ARDD) genes explained 90% of the total AR coding burden, and this was not significantly different between probands with genetically-inferred European versus non-European ancestries. Approximately half the burden in these established genes was explained by variants not already reported as pathogenic in ClinVar. We estimated that ∼1% of undiagnosed patients in both cohorts were attributable to damaging biallelic genotypes involving missense variants in established ARDD genes, highlighting the challenge in interpreting these. By testing for gene-specific enrichment of damaging biallelic genotypes, we identified two novel ARDD genes passing Bonferroni correction, KBTBD2 (p=1x10 -7 ) and CRELD1 (p=9x10 -8 ). Several other novel or recently-reported candidate genes were identified at a more lenient 5% false-discovery rate, including ZDHHC16 and HECTD4 . This study expands our understanding of the genetic architecture of DDs across erse genetically-inferred ancestry groups and suggests that improving strategies for interpreting missense variants in known ARDD genes may allow us to diagnose more patients than discovering the remaining genes.
Publisher: Springer Science and Business Media LLC
Date: 09-12-2021
Publisher: Cold Spring Harbor Laboratory
Date: 25-04-2023
DOI: 10.1101/2023.04.20.23288860
Abstract: Recent work has revealed an important role for rare, incompletely penetrant inherited coding variants in neurodevelopmental disorders (NDDs). Additionally, we have previously shown that common variants contribute to risk for rare NDDs. Here, we investigate whether common variants exert their effects by modifying gene expression, using multi- cis -expression quantitative trait loci ( cis -eQTL) prediction models. We first performed a transcriptome-wide association study for NDDs using 6,987 probands from the Deciphering Developmental Disorders (DDD) study and 9,720 controls, and found one gene, RAB2A , that passed multiple testing correction (p = 6.7×10 −7 ). We then investigated whether cis -eQTLs modify the penetrance of putatively damaging, rare coding variants inherited by NDD probands from their unaffected parents in a set of 1,700 trios. We found no evidence that unaffected parents transmitting putatively damaging coding variants had higher genetically-predicted expression of the variant-harboring gene than their child. In probands carrying putatively damaging variants in constrained genes, the genetically-predicted expression of these genes in blood was lower than in controls (p = 2.7×10 −3 ). However, results for proband-control comparisons were inconsistent across different sets of genes, variant filters and tissues. We find limited evidence that common cis -eQTLs modify penetrance of rare coding variants in a large cohort of NDD probands.
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: Cold Spring Harbor Laboratory
Date: 27-09-2018
DOI: 10.1101/426163
Abstract: East London Genes & Health (ELGH) is a large scale, community genomics and health study (to date ,000 volunteers target 100,000 volunteers). ELGH was set up in 2015 to gain deeper understanding of health and disease, and underlying genetic influences, in British-Bangladeshi and British-Pakistani people living in east London. ELGH prioritises studies in areas important to, and identified by, the community it represents. Current priorities include cardiometabolic diseases and mental illness, these being of notably high prevalence and severity. However studies in any scientific area are possible, subject to community advisory group and ethical approval. ELGH combines health data science (using linked UK National Health Service (NHS) electronic health record data) with exome sequencing and SNP array genotyping to elucidate the genetic influence on health and disease, including the contribution from high rates of parental relatedness on rare genetic variation and homozygosity (autozygosity), in two understudied ethnic groups. Linkage to longitudinal health record data enables both retrospective and prospective analyses. Through Stage 2 studies, ELGH offers researchers the opportunity to undertake recall-by-genotype and/or recall-by-phenotype studies on volunteers. Sub-cohort, trial-within-cohort, and other study designs are possible. ELGH is a fully collaborative, open access resource, open to academic and life sciences industry scientific research partners.
Publisher: Cold Spring Harbor Laboratory
Date: 23-03-2020
DOI: 10.1101/2020.03.18.20037960
Abstract: Over 130 X-linked genes have been robustly associated with developmental disorders (DDs), and X-linked causes have been hypothesised to underlie the higher DD rates in males. We evaluated the burden of X-linked coding variation in 11,046 DD patients, and found a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We developed an improved strategy to detect novel X-linked DDs and identified 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known DD-associated genes. Importantly, we estimated that, in male probands, only 13% of inherited rare missense variants in known DD-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for in idual X-linked disorders.
Publisher: Cold Spring Harbor Laboratory
Date: 25-08-2023
DOI: 10.1101/2023.08.23.23294497
Abstract: Correct classification of type 1 (T1D) and type 2 diabetes (T2D) is challenging due to overlapping clinical features and the increasingly early onset of T2D, particularly in South Asians. We used polygenic risk scores (PRSs) in a British Bangladeshi and Pakistani population with diabetes to estimate the proportion and misclassification rate of T1D in insulin-treated in iduals with ambiguous features. Using linked health record from the Genes & Health cohort (n=38,344) we defined four groups: 31 T1D cases, 1,842 T2D cases, and after excluding these, 839 insulin-treated in iduals with ambiguous features and 5,174 controls. Combining these with 307 confirmed T1D cases and 307 controls from India, we calculated ancestry-corrected PRSs for T1D and T2D, with which we estimated the proportion of T1D cases within the ambiguous group and evaluated misclassification. We estimated that the prevalence of T1D was ∼6% within the ambiguous group, or ∼4.5% within the subset who had T2D codes in their health records. We saw no significant association between the T1D or T2D PRS and BMI at diagnosis, time to insulin, or the presence of T1D or T2D diagnostic codes amongst the T2D or ambiguous cases. We estimate that 4.5% of British Pakistanis and Bangladeshis with diabetes who are treated with insulin and have ambiguous clinical features have been classified incorrectly in their health records, and in fact have T1D. These findings have significant implications for the delivery of optimal clinical care at population level.
Publisher: Cold Spring Harbor Laboratory
Date: 02-02-2023
DOI: 10.1101/2023.02.01.23285346
Abstract: Autozygosity is associated with rare Mendelian disorders and clinically-relevant quantitative traits. We investigated associations between F ROH (fraction of the genome in runs of homozygosity) and common diseases in Genes & Health (N=23,978 British South Asians), UK Biobank (N=397,184), and 23andMe, Inc. We show that restricting analysis to offspring of first cousins is an effective way of removing confounding due to social/environmental correlates of F ROH . Within this group in G& H+UK Biobank, we found experiment-wide significant associations between F ROH and twelve common diseases. We replicated the associations with type 2 diabetes (T2D) and post-traumatic stress disorder via between-sibling analysis in 23andMe (median N=480,282). We estimated that autozygosity due to consanguinity accounts for 5-18% of T2D cases amongst British Pakistanis. Our work highlights the possibility of widespread non-additive effects on common diseases and has important implications for global populations with high rates of consanguinity.
Publisher: Springer Science and Business Media LLC
Date: 21-09-2020
DOI: 10.1038/S41467-020-20852-3
Abstract: Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for in idual X-linked disorders.
Publisher: Cold Spring Harbor Laboratory
Date: 12-2022
DOI: 10.1101/2022.11.30.22282929
Abstract: Preecl sia and gestational hypertension are common pregnancy complications associated with adverse maternal and offspring outcomes. Current tools for prediction, prevention, and treatment are limited. We tested the association of maternal DNA sequence variants with preecl sia in 20,064 cases and 703,117 controls and with gestational hypertension in 11,027 cases and 412,788 controls across discovery and follow-up cohorts using multi-ancestry meta-analysis. Altogether, we identified 18 independent loci associated with preecl sia/ecl sia and/or gestational hypertension, 12 of which are novel (e.g., MTHFR-CLCN6 , WNT3A , NPR3 , PGR , and RGL3 ), including two loci ( PLCE1 , FURIN ) identified in multi-trait analysis. Identified loci highlight the role of natriuretic peptide signaling, angiogenesis, renal glomerular function, trophoblast development, and immune dysregulation. We derived genome-wide polygenic risk scores that predicted preecl sia/ecl sia and gestational hypertension in external datasets, independent of first trimester risk markers. Collectively, these findings provide mechanistic insights into the hypertensive disorders of pregnancy and advance pregnancy risk stratification.
Publisher: Cold Spring Harbor Laboratory
Date: 02-10-2020
DOI: 10.1101/2020.10.02.20194241
Abstract: Structural Variation (SV) describes a broad class of genetic variation greater than 50bps in size. SVs can cause a wide range of genetic diseases and are prevalent in rare developmental disorders (DD). Patients presenting with DD are often referred for diagnostic testing with chromosomal microarrays (CMA) to identify large copy-number variants (CNVs) and/or with single gene, gene-panel, or exome sequencing (ES) to identify single nucleotide variants, small insertions/deletions, and CNVs. However, patients with pathogenic SVs undetectable by conventional analysis often remain undiagnosed. Consequently, we have developed the novel tool ‘InDelible’, which interrogates short-read sequencing data for split-read clusters characteristic of SV breakpoints. We applied InDelible to 13,438 probands with severe DD recruited as part of the Deciphering Developmental Disorders (DDD) study and discovered 64 rare, damaging variants in genes previously associated with DD missed by standard SNV, InDel or CNV discovery approaches. Clinical review of these 64 variants determined that about half (30/64) were plausibly pathogenic. InDelible was particularly effective at ascertaining variants between 21-500 bps in size, and increased the total number of potentially pathogenic variants identified by DDD in this size range by 42.3%. Of particular interest were seven confirmed de novo variants in MECP2 which represent 35.0% of all de novo protein truncating variants in MECP2 among DDD patients. InDelible provides a framework for the discovery of pathogenic SVs that are likely missed by standard analytical workflows and has the potential to improve the diagnostic yield of ES across a broad range of genetic diseases.
Publisher: Cold Spring Harbor Laboratory
Date: 13-10-2017
DOI: 10.1101/201533
Abstract: Large exome-sequencing datasets offer an unprecedented opportunity to understand the genetic architecture of rare diseases, informing clinical genetics counseling and optimal study designs for disease gene identification. We analyzed 7,448 exome-sequenced families from the Deciphering Developmental Disorders study, and, for the first time, estimated the causal contribution of recessive coding variation exome-wide. We found that the proportion of cases attributable to recessive coding variants is surprisingly low in patients of European ancestry, at only 3.6%, versus 50% of cases explained by de novo coding mutations. Surprisingly, we found that, even in European probands with affected siblings, recessive coding variants are only likely to explain ~12% of cases. In contrast, they account for 31% of probands with Pakistani ancestry due to elevated autozygosity. We tested every gene for an excess of damaging homozygous or compound heterozygous genotypes and found three genes that passed stringent Bonferroni correction: EIF3F , KDM5B , and THOC6 . EIF3F is a novel disease gene, and KDM5B has previously been reported as a dominant disease gene. KDM5B appears to follow a complex mode of inheritance, in which heterozygous loss-of-function variants (LoFs) show incomplete penetrance and biallelic LoFs are fully penetrant. Our results suggest that a large proportion of undiagnosed developmental disorders remain to be explained by other factors, such as noncoding variants and polygenic risk.
Publisher: Elsevier BV
Date: 10-2023
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: Cold Spring Harbor Laboratory
Date: 28-01-2019
DOI: 10.1101/530881
Abstract: Human genetics has informed the clinical development of new drugs, and is beginning to influence the selection of new drug targets. Large-scale DNA sequencing studies have created a catalogue of naturally occurring genetic variants predicted to cause loss of function in human genes, which in principle should provide powerful in vivo models of human genetic “knockouts” to complement model organism knockout studies and inform drug development. Here, we consider the use of predicted loss-of-function (pLoF) variation catalogued in the Genome Aggregation Database (gnomAD) for the evaluation of genes as potential drug targets. Many drug targets, including the targets of highly successful inhibitors such as aspirin and statins, are under natural selection at least as extreme as known haploinsufficient genes, with pLoF variants almost completely depleted from the population. Thus, metrics of gene essentiality should not be used to eliminate genes from consideration as potential targets. The identification of in idual humans harboring “knockouts” (biallelic gene inactivation), followed by in idual recall and deep phenotyping, is highly valuable to study gene function. In most genes, pLoF alleles are sufficiently rare that ascertainment will be largely limited to heterozygous in iduals in outbred populations. S ling of erse bottlenecked populations and consanguineous in iduals will aid in identification of total “knockouts”. Careful filtering and curation of pLoF variants in a gene of interest is necessary in order to identify true LoF in iduals for follow-up, and the positional distribution or frequency of true LoF variants may reveal important disease biology. Our analysis suggests that the value of pLoF variant data for drug discovery lies in deep curation informed by the nature of the drug and its indication, as well as the biology of the gene, followed by recall-by-genotype studies in targeted populations.
Publisher: Cold Spring Harbor Laboratory
Date: 16-10-2019
DOI: 10.1101/797787
Abstract: De novo mutations (DNMs) in protein-coding genes are a well-established cause of developmental disorders (DD). However, known DD-associated genes only account for a minority of the observed excess of such DNMs. To identify novel DD-associated genes, we integrated healthcare and research exome sequences on 31,058 DD parent-offspring trios, and developed a simulation-based statistical test to identify gene-specific enrichments of DNMs. We identified 285 significantly DD-associated genes, including 28 not previously robustly associated with DDs. Despite detecting more DD-associated genes than in any previous study, much of the excess of DNMs of protein-coding genes remains unaccounted for. Modelling suggests that over 1,000 novel DD-associated genes await discovery, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of dominant DDs.
Publisher: Springer Science and Business Media LLC
Date: 17-08-2023
Publisher: Springer Science and Business Media LLC
Date: 23-03-2022
DOI: 10.1038/S41586-022-04549-9
Abstract: Genome-wide sequencing of human populations has revealed substantial variation among genes in the intensity of purifying selection acting on damaging genetic variants
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: 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: Cold Spring Harbor Laboratory
Date: 28-05-2020
DOI: 10.1101/2020.05.26.116111
Abstract: Genome-wide sequencing of human populations has revealed substantial variation among genes in the intensity of purifying selection acting on damaging genetic variants 1 . While genes under the strongest selective constraint are highly enriched for associations with Mendelian disorders, most of these genes are not associated with disease and therefore the nature of the selection acting on them is not known 2 . Here we show that genetic variants that damage these genes are associated with markedly reduced reproductive success, primarily due to increased childlessness, with a stronger effect in males than in females. We present evidence that increased childlessness is likely mediated by genetically associated cognitive and behavioural traits, which may mean male carriers are less likely to find reproductive partners. This reduction in reproductive success may account for 20% of purifying selection against heterozygous variants that ablate protein-coding genes. While this genetic association could only account for a very minor fraction of the overall likelihood of being childless (less than 1%), especially when compared to more influential sociodemographic factors, it may influence how genes evolve over time.
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.
Publisher: Springer Science and Business Media LLC
Date: 26-05-2023
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Hilary Martin.