Search

Background How obesity earlier in life impacts upon mobility dysfunctions in late life is not well understood. Pernicious effects of excess weight on the musculoskeletal system and mobility dysfunctions are well-recognized. However, increasingly more data support the link of obesity to overall motor defects that are regulated in the brain. Objectives To assess the causal relationship between body mass index (BMI) at midlife and performance of the Timed Up-and-Go test (TUG) in late life among a population-based longitudinal cohort of Chinese adults living in Singapore. Methods We evaluated genetic predispositions for BMI in 8342 participants who were followed up from measurement of BMI at average 53 years, to TUG test (as a functional mobility measure) 20 years later. Results A robust 75.83% of genetically determined BMI effects on late life TUG scores was mediated through midlife BMI (Pindirect−effect = 9.24×10− 21). Utilizing Mendelian randomization, we demonstrated a causal effect between BMI and functional mobility in late life (βIVW = 0.180, PIVW = 0.001). Secondary gene enrichment evaluations highlighted down-regulation of genes at BMI risk loci that were correlated with poorer functional mobility in the substantia nigra and amygdala regions as compared to all other tissues. These genes also exhibit differential expression patterns during human brain development. Conclusions We report a causal effect of obesity on mobility dysfunction. Our findings highlight potential neuronal dysfunctions in regulating predispositions on the causal pathway from obesity to mobility dysfunction.

The therapeutic efficacy of tamoxifen is predominantly mediated by its active metabolites 4-hydroxy-tamoxifen and endoxifen, whose formation is catalyzed by the polymorphic cytochrome P450 2D6 (CYP2D6). Yet, known CYP2D6 polymorphisms only partially determine metabolite concentrations in vivo. We performed the first cross-ancestry genome-wide association study with well-characterized patients of European, Middle-Eastern, and Asian descent (N = 497) to identify genetic factors impacting active and parent metabolite formation. Genome-wide significant variants were functionally evaluated in an independent liver cohort (N = 149) and in silico. Metabolite prediction models were validated in two independent European breast cancer cohorts (N = 287, N = 189). Within a single 1-megabase (Mb) region of chromosome 22q13 encompassing the CYP2D6 gene, 589 variants were significantly associated with tamoxifen metabolite concentrations, particularly endoxifen and metabolic ratio (MR) endoxifen/N-desmethyltamoxifen (minimal P = 5.4E-35 and 2.5E-65, respectively). Previously suggested other loci were not confirmed. Functional analyses revealed 66% of associated, mostly intergenic variants to be significantly correlated with hepatic CYP2D6 activity or expression (ρ = 0.35 to -0.52), and six hotspot regions in the extended 22q13 locus impacting gene regulatory function. Machine learning models based on hotspot variants (N = 12) plus CYP2D6 activity score (AS) increased the explained variability (~ 9%) compared with AS alone, explaining up to 49% (median R2 ) and 72% of the variability in endoxifen and MR endoxifen/N-desmethyltamoxifen, respectively. Our findings suggest that the extended CYP2D6 locus at 22q13 is the principal genetic determinant of endoxifen plasma concentration. Long-distance haplotypes connecting CYP2D6 with adjacent regulatory sites and nongenetic factors may account for the unexplained portion of variability.

Background: Nicotine metabolism is a major factor in nicotine dependence, with approximately 70% to 80% of nicotine metabolized to cotinine in Caucasians. Cotinine formation is catalyzed primarily by CYP2A6, which also converts cotinine to trans-3′-hydroxycotinine (3HC). The goal of the present study was to examine the effects of CYP2A6 deficiency on nicotine metabolism profiles in vivo and the importance of genetic variants in nicotine-metabolizing enzyme genes on urinary nicotine metabolites levels. Methods: Urine samples from 722 smokers who participated in the Singapore Chinese Health Study were analyzed using UPLC-MS/MS to detect nicotine and eight of its urinary metabolites, and a total of 58 variants in 12 genes involved in nicotine metabolism were investigated in 475 of these subjects with informative genotyping data. Results: Urine samples stratified by the ratio of 3HC/cotinine exhibited a 7-fold increase in nicotine-N’-oxide, a 6-fold increase in nicotine-Glucuronide (Gluc), and a 5-fold decrease in 3HC-Gluc when comparing the lower versus upper 3HC/cotinine ventiles. Significant (P < 0.0001) associations were observed between functional metabolizing enzyme genotypes and levels of various urinary nicotine metabolites, including CYP2A6 genotype and levels of nicotine, nicotine-Gluc, nicotine-N’-oxide and 3HC, UGT2B10 genotype and levels of cotinine, nicotine-Gluc and cotinine-Gluc, UGT2B17 genotype and levels of 3HC-Gluc, FMO3 genotype and levels of nicotine-N’-oxide, and CYP2B6 genotype and levels of nicotine-N’-oxide and 4-hydroxy-4-(3-pyridyl)-butanoic acid. Conclusions: These data suggest that several pathways are important in nicotine metabolism. Impact: Genotype differences in several nicotine-metabolizing enzyme pathways may potentially lead to differences in nicotine dependence and smoking behavior and cessation.

BACKGROUND: Understanding the genetic predisposition to cardiovascular disease (CVD) may help to improve clinical intervention strategies. Lifestyle factors, such as diet, may differ among ethnic groups and may, in turn, modify individuals’ risks to diseases. OBJECTIVES: We examined the genetic predisposition to ever smoking in relation to CVD mortality and assessed whether such an association could be modified by dietary intake. METHODS: A total of 23,760 Chinese adults from the Singapore Chinese Heath Study who were free of cancer and CVD at recruitment (1993–1998) were included in the study. A weighted genetic risk score (wGRS) was calculated to define the genetically determined regular smoking behavior (never or ever). Multivariable-adjusted Cox regression models were used to assess the association between the wGRS and CVD mortality. We also conducted a 1-sample Mendelian randomization analysis for ever smoking and CVD mortality. RESULTS: Over a mean of 22.6 years of follow-up, 2301 CVD deaths were identified. A genetic predisposition to ever smoking was significantly associated with CVD mortality; the multivariable-adjusted HR of CVD mortality was 1.07 (95% CI: 1.03–1.12), with a per-SD increment in the wGRS. However, the Mendelian randomization analysis did not support a causal relationship between ever smoking and CVD mortality (OR, 1.13; 95% CI: 0.87–1.45). Additionally, the Dietary Approaches to Stop Hypertension (DASH) score significantly modified the association between the smoking wGRS and CVD mortality; the association between a genetic predisposition to smoking and CVD mortality was only observed among individuals with a low DASH score (P-interaction = 0.004). CONCLUSIONS: A genetic predisposition to smoking was associated with CVD mortality in the Chinese population. In addition, we detected a significant interaction showing higher CVD mortality related to genetically determined smoking among those with lower DASH scores.

With lowering costs of sequencing and genetic profiling techniques, genetic drivers can now be detected readily in tumors but current prognostic models for Natural-killer/T cell lymphoma (NKTCL) have yet to fully leverage on them for prognosticating patients. Here, we used next-generation sequencing to sequence 260 NKTCL tumors, and trained a genomic prognostic model (GPM) with the genomic mutations and survival data from this retrospective cohort of patients using LASSO Cox regression. The GPM is defined by the mutational status of 13 prognostic genes and is weakly correlated with the risk-features in International Prognostic Index (IPI), Prognostic Index for Natural-Killer cell lymphoma (PINK), and PINK-Epstein-Barr virus (PINK-E). Cox-proportional hazard multivariate regression also showed that the new GPM is independent and significant for both progression-free survival (PFS, HR: 3.73, 95% CI 2.07-6.73; p

Telomere attrition is an established ageing biomarker and shorter peripheral blood leukocyte telomere length has been associated with increased risks of respiratory diseases. However, whether telomere length in disease-relevant sputum immune cells of chronic respiratory disease patients is shortened and which pathways are dysfunctional are not clear. Here we measured telomere length from sputum samples of bronchiectasis and asthmatic subjects and determined that telomere length in sputum of bronchiectasis subjects was significantly shorter (Beta = - 1.167, P

The rich diversity of morphology and behavior displayed across primate species provides an informative context in which to study the impact of genomic diversity on fundamental biological processes. Analysis of that diversity provides insight into long-standing questions in evolutionary and conservation biology, and is urgent given severe threats these species are facing. Here, we present high coverage whole-genome data from 233 primate species representing 86% of genera and all 16 families. This dataset was used, together with fossil calibration, to create a nuclear DNA phylogeny and to reassess evolutionary divergence times among primate clades. We found within-species genetic diversity across families and geographic regions to be associated with climate and sociality, but not with extinction risk. Furthermore, mutation rates differ across species, potentially influenced by effective population sizes. Lastly, we identified extensive recurrence of missense mutations previously thought to be human-specific. This study will open a wide range of research avenues for future primate genomic research.One-Sentence SummaryThe whole genome sequences of 233 primate species provide insight into the determinants of genetic diversity, phylogenomics, and human uniqueness.

INTRODUCTIONMillions of people have received genome and exome sequencing to date, a collective effort that has illuminated for the first time the vast catalog of small genetic differences that distinguish us as individuals within our species. However, the effects of most of these genetic variants remain unknown, limiting their clinical utility and actionability. New approaches that can accurately discern disease-causing from benign mutations and interpret genetic variants on a genome-wide scale would constitute a meaningful initial step towards realizing the potential of personalized genomic medicine.RATIONALEAs a result of the short evolutionary distance between humans and nonhuman primates, our proteins share near-perfect amino acid sequence identity. Hence, the effects of a protein-altering mutation found in one species are likely to be concordant in the other species. By systematically cataloging common variants of nonhuman primates, we aimed to annotate these variants as being unlikely to cause human disease as they are tolerated by natural selection in a closely related species. Once collected, the resulting resource may be applied to infer the effects of unobserved variants across the genome using machine learning.RESULTSFollowing the strategy outlined above we obtained whole-genome sequencing data for 809 individuals from 233 primate species and cataloged 4.3 million common missense variants. We confirmed that human missense variants seen in at least one nonhuman primate species were annotated as benign in the ClinVar clinical variant database in 99% of cases. By contrast, common variants from mammals and vertebrates outside the primate lineage were substantially less likely to be benign in the ClinVar database (71 to 87% benign), restricting this strategy to nonhuman primates. Overall, we reclassified more than 4 million human missense variants of previously unknown consequence as likely benign, resulting in a greater than 50-fold increase in the number of annotated missense variants compared to existing clinical databases.To infer the pathogenicity of the remaining missense variants in the human genome, we constructed PrimateAI-3D, a semisupervised 3D-convolutional neural network that operates on voxelized protein structures. We trained PrimateAI-3D to separate common primate variants from matched control variants in 3D space as a semisupervised learning task. We evaluated the trained PrimateAI-3D model alongside 15 other published machine learning methods on their ability to distinguish between benign and pathogenic variants in six different clinical benchmarks and demonstrated that PrimateAI-3D outperformed all other classifiers in each of the tasks.CONCLUSIONOur study addresses one of the key challenges in the variant interpretation field, namely, the lack of sufficient labeled data to effectively train large machine learning models. By generating the most comprehensive primate sequencing dataset to date and pairing this resource with a deep learning architecture that leverages 3D protein structures, we were able to achieve meaningful improvements in variant effect prediction across multiple clinical benchmarks. Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole-genome sequencing data for 809 individuals from 233 primate species and identified 4.3 million common protein-altering variants with orthologs in humans. We show that these variants can be inferred to have nondeleterious effects in humans based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases.

It is difficult to identify people with nonalcoholic fatty liver disease (NAFLD) who are at high risk for developing hepatocellular carcinoma (HCC). A polygenic risk score (PRS) for hepatic fat (HFC-PRS) derived from non-Asians has been reported to be associated with HCC risk in European populations. However, population-level data of this risk in Asian populations are lacking. Utilizing resources from 24,333 participants of the Singapore Chinese Health Study (SCHS), we examined the relationship between the HFC-PRS and HCC risk. In addition, we constructed and evaluated a NAFLD-related PRS (NAFLD-PRS) with HCC risk in the SCHS. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of HCC incidence with both HFC-PRS and NAFLD-PRS. The HFC-PRS and NAFLD-PRS were highly correlated (Spearman r = 0.79, p 0.001). The highest quartiles of both the HFC-PRS and the NAFLD-PRS were associated with significantly increased risk of HCC with HR of 2.39 (95% CI 1.51, 3.78) and 1.77 (95% CI 1.15, 2.73), respectively, compared with their respective lowest quartile. Conclusion: The PRS for hepatic fat content or NAFLD may be useful for assessing HCC risk in both Asian and European populations. The findings of this and prior studies support a potential causal role of genetically determined NAFLD in HCC development.

STUDY QUESTION Are there genetic variants that interact with smoking to reduce reproductive lifespan in East-Asian women? SUMMARY ANSWER Our study corroborates several recently identified genetic loci associated with reproductive lifespan and highlights specific genetic predispositions that may interact with smoking status to adversely affect reproductive lifespan in East-Asian women. WHAT IS KNOWN ALREADY Epidemiological data as well as evaluations on genetic predisposition to smoke indicate on the importance of smoking in adverse effects on reproductive lifespan in women. However, there are no previous smoking and gene interaction studies for reproductive traits in East-Asian women. STUDY DESIGN, SIZE, DURATION This population-based prospective cohort study comprised 11 643 East-Asian Chinese women with overlapping genome-wide genotyping and reproductive data. PARTICIPANTS/MATERIALS, SETTING, METHODS We performed a genome-wide association study for reproductive lifespan in women (n = 11 643) from the Singapore Chinese Health Study (SCHS) and carried out a genome-wide interaction study to identify loci that interacted with smoking status to affect age of natural menopause and reproductive-time. MAIN RESULTS AND THE ROLE OF CHANCE Two known loci associated with menopause, rs113430717 (near HMCES, chromosome 3, Pmeta = 5.72 × 10−15) and rs3020136 (near RAD21, chromosome 8, Pmeta = 1.38 × 10−8) were observed beyond genome-wide levels of association with age at menopause in this study. For reproductive lifespan, the genome-wide association observed at rs79784106 (chromosome 3, Pmeta = 5.05 × 10−12) was in linkage disequilibrium with the menopause lead single-nucleotide polymorphism (SNP) (rs113430717). Four additional loci, first reported to be associated with menopause, were also associated with reproductive lifespan in our study (PAdj between 7.42 × 10−5 to 4.51 × 10−3). A significant interaction was observed between smoking and an East-Asian specific SNP, rs140146885, for reduced reproductive lifespan, per copy of the minor C allele (beta = −1.417 years, Pinteraction = 2.31 × 10−10). This interaction was successfully replicated in additional independent samples (beta = −1.389 years, Pinteraction = 6.78 × 10−3). Another known variant associated with menopause, rs11031006 (near FSHB), was also observed to interact with smoking status to reduce age at menopause in our dataset (beta = −0.450 years, Padj = 0.042). LIMITATIONS, REASONS FOR CAUTION The modest sample size of the replication datasets used likely affected the statistical power to firmly replicate all identified novel loci observed in our smoking interaction analyses. WIDER IMPLICATIONS OF THE FINDINGS Age of natural menopause and reproductive lifespan have clear genetic predispositions with distinct ethnic differences, and they may be adversely truncated by lifestyle factors such as smoking, which can pose a significant impact on the reproductive lifespan and future health outcomes in women. STUDY FUNDING/COMPETING INTEREST(S) The Singapore Chinese Health Study is funded by the National Medical Research Council, Singapore (NMRC/CIRG/1456/2016), National Institutes of Health (R01 CA144034 and UM1 CA182876) and National Research Foundation, Singapore (Project Number 370062002). W.-P.K. is supported by the National Medical Research Council, Singapore (MOH-CSASI19nov-0001). The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. The authors do not report conflicts of interest. TRIAL REGISTRATION NUMBER N/A.

Purpose Non-European populations are under-represented in genetics studies, hindering clinical implementation of breast cancer polygenic risk scores (PRSs). We aimed to develop PRSs using the largest available studies of Asian ancestry and to assess the transferability of PRS across ethnic subgroups. Methods The development data set comprised 138,309 women from 17 case-control studies. PRSs were generated using a clumping and thresholding method, lasso penalized regression, an Empirical Bayes approach, a Bayesian polygenic prediction approach, or linear combinations of multiple PRSs. These PRSs were evaluated in 89,898 women from 3 prospective studies (1592 incident cases). Results The best performing PRS (genome-wide set of single-nucleotide variations [formerly single-nucleotide polymorphism]) had a hazard ratio per unit SD of 1.62 (95% CI = 1.46-1.80) and an area under the receiver operating curve of 0.635 (95% CI = 0.622-0.649). Combined Asian and European PRSs (333 single-nucleotide variations) had a hazard ratio per SD of 1.53 (95% CI = 1.37-1.71) and an area under the receiver operating curve of 0.621 (95% CI = 0.608-0.635). The distribution of the latter PRS was different across ethnic subgroups, confirming the importance of population-specific calibration for valid estimation of breast cancer risk. Conclusion PRSs developed in this study, from association data from multiple ancestries, can enhance risk stratification for women of Asian ancestry.

Host cell chromatin changes are thought to play an important role in the pathogenesis of infectious diseases. Here we describe a histone acetylome-wide association study (HAWAS) of an infectious disease, on the basis of genome-wide H3K27 acetylation profiling of peripheral blood granulocytes and monocytes from persons with active Mycobacterium tuberculosis (Mtb) infection and healthy controls. We detected >2,000 differentially acetylated loci in either cell type in a Singapore Chinese discovery cohort (n = 46), which were validated in a subsequent multi-ethnic Singapore cohort (n = 29), as well as a longitudinal cohort from South Africa (n = 26), thus demonstrating that HAWAS can be independently corroborated. Acetylation changes were correlated with differential gene expression. Differential acetylation was enriched near potassium channel genes, including KCNJ15, which modulates apoptosis and promotes Mtb clearance in vitro. We performed histone acetylation quantitative trait locus (haQTL) analysis on the dataset and identified 69 candidate causal variants for immune phenotypes among granulocyte haQTLs and 83 among monocyte haQTLs. Our study provides proof-of-principle for HAWAS to infer mechanisms of host response to pathogens.

Objective To develop a hypothesis-free model that best predicts response to MTX drug in RA patients utilizing biologically meaningful genetic feature selection of potentially functional single nucleotide polymorphisms (pfSNPs) through robust machine learning (ML) feature selection methods. Methods MTX-treated RA patients with known response were divided in a 4:1 ratio into training and test sets. From the patients’ exomes, potential features for classifier prediction were identified from pfSNPs and non-genetic factors through ML using recursive feature elimination with cross-validation incorporating the random forest classifier. Feature selection was repeated on random subsets of the training cohort, and consensus features were assembled into the final feature set. This feature set was evaluated for predictive potential using six ML classifiers, first by cross-validation within the training set, and finally by analysing its performance with the unseen test set. Results The final feature set contains 56 pfSNPs and five non-genetic factors. The majority of these pfSNPs are located in pathways related to RA pathogenesis or MTX action and are predicted to modulate gene expression. When used for training in six ML classifiers, performance was good in both the training set (area under the curve: 0.855–0.916; sensitivity: 0.715–0.892; and specificity: 0.733–0.862) and the unseen test set (area under the curve: 0.751–0.826; sensitivity: 0.581–0.839; and specificity: 0.641–0.923). Conclusion Sensitive and specific predictors of MTX response in RA patients were identified in this study through a novel strategy combining biologically meaningful and machine learning feature selection and training. These predictors may facilitate better treatment decision-making in RA management.

BackgroundThe purpose of this study was to assess if single nucleotide polymorphisms (SNPs) in lung mucins MUC5B and MUC5AC are associated with Mycobacterium tuberculosis outcomes.MethodsIndependent SNPs in MUC5B and MUC5AC (genotyped by Illumina HumanOmniExpress array) were assessed for associations with tumor necrosis factor (TNF) concentrations (measured by immunoassay) in cerebral spinal fluid (CSF) from tuberculous meningitis (TBM) patients. SNPs associated with CSF TNF concentrations were carried forward for analyses of pulmonary and meningeal tuberculosis susceptibility and TBM mortality.ResultsMUC5AC SNP rs28737416 T allele was associated with lower CSF concentrations of TNF (P = 1.8 × 10−8) and IFN-γ (P = 2.3 × 10−6). In an additive genetic model, rs28737416 T/T genotype was associated with higher susceptibility to TBM (odds ratio [OR], 1.24; 95% confidence interval [CI], 1.03–1.49; P = .02), but not pulmonary tuberculosis (OR, 1.11, 95% CI, .98–1.25; P = .10). TBM mortality was higher among participants with the rs28737416 T/T and T/C genotypes (35/119, 30.4%) versus the C/C genotype (11/89, 12.4%; log-rank P = .005) in a Vietnam discovery cohort (n = 210), an independent Vietnam validation cohort (n = 87; 9/87, 19.1% vs 1/20, 2.5%; log-rank P = .02), and an Indonesia validation cohort (n = 468, 127/287, 44.3% vs 65/181, 35.9%; log-rank P = .06).ConclusionsMUC5AC variants may contribute to immune changes that influence TBM outcomes.

One of the promises of precision medicine is to understand and act on inter-individual genetic differences in drug responses. SNPdrug3D contains the complete genomic landscape of missense single nucleotide variants (SNV) across the human proteome and at population-wide level that could affect drug binding. In the Singapore SG10K Health and global gnomAD cohorts, comprising variations in over 80,000 individuals, we identified ~ 1.17 million variants mapped to residues near bound drug molecules in protein-drug complexes relative to ~ 6000 drug molecules and experimentally verified effects of selected SNVs, including previously uncharacterized variants, on drug binding in relevant proteins ranging from kinases to cytochrome P450s (CYPs). The latter led to a specific predictor for interpreting variants in the CYP family that vastly outperforms existing tools in the prediction of pharmacogenetic effects. By placing variants and drugs in structural context, SNPdrug3D aids drug development by early flagging of resistance potential through population-specific variability.

Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry metaanalysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk., United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Heart Lung & Blood Institute (NHLBI) R01HL127564 R01HL142711, Wellcome Trust 201543/B/16/Z 202802/Z/16/Z, European Commission HEALTH-F2-2013-601456 608765 786833, TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation NNF15CC0018486, American Diabetes Association 1-19-ICTS-068, Academy of Finland 312062 Finnish Foundation for Cardiovascular Research, Sigrid Juselius Foundation, Finnish innovation fund Sitra (EW) Finska Lakaresallskapet, American Heart Association 15POST24470131 17POST33650016, University of Bristol NIHR Biomedical Research Centre BRC-1215-2001, MRC & WT 217065/Z/19/Z, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) MC_UU_00011, CRUK Integrative Cancer Epidemiology Programme C18281/A19169, Medical Research Council UK (MRC) MC_UU_00011/1, UK National Institute for Health Research Academic Clinical Fellowship, American Heart Association 18CDA34110116, Miguel Servet contract from the ISCIII Spanish Health Institute CP17/00142, European Social Fund (ESF), Westlake Education Foundation, British Heart Foundation FS/14/66/3129 Z01HG200362 R01HL142302 R01HL105756

Background and Aim Chronic hepatitis C virus (HCV) infection, long‐term alcohol use, cigarette smoking, and obesity are the major risk factors for hepatocellular carcinoma (HCC) in the United States, but the disease risk varies substantially among individuals with these factors, suggesting host susceptibility to and gene–environment interactions in HCC. To address genetic susceptibility to HCC, we conducted a genome‐wide association study (GWAS). Methods Two case‐control studies on HCC were conducted in the United States. DNA samples were genotyped using the Illumian microarray chip with over 710 000 single nucleotide polymorphisms (SNPs). We compared these SNPs between 705 HCC cases and 1455 population controls for their associations with HCC and verified our findings in additional studies. Results In this GWAS, we found that two SNPs were associated with HCC at P, Genome‐wide association study (GWAS) showed that five SNPs in 22q13.31, three in PNPLA3 (rs2281135, rs2896019, and 4823173) and two in SAMM50 (rs3761472 and rs3827385), were associated with HCC in the United States.

Whole genome sequencing (WGS) and phenotypic drug susceptibility testing was performed on a collection of 2,542Mycobacterium tuberculosis (Mtb)isolates from tuberculosis (TB) patients recruited in Ho Chi Minh City (HCMC), Vietnam, to investigateMtbdiversity, the prevalence and phylodynamics of drug resistance, andin silicoresistance prediction with sequencing data. Amongst isolates tested phenotypically against first-line drugs, we observed high rates of streptomycin [STR, 37.7% (N=573/1,520)] and isoniazid resistance [INH, 25.7% (N=459/1,786)], and lower rates of resistance to rifampicin [RIF, 4.9% (N=87/1,786)] and ethambutol [EMB, 4.2% (N=75/1,785)]. Resistance to STR and INH was predicted moderately well when applying the TB-Profiler algorithm to WGS data (sensitivities of 0.81 and 0.87 respectively), while resistance to RIF and EMB was predicted relatively poorly (sensitivities of 0.70 and 0.44 respectively). Rates of multidrug-resistance [(MDR, 3.9% (N=69/1,786)], and resistance to a number of second-line drugs [Para-aminosalicylic acid (29.6% N=79/267), Amikacin (15.4% N=41/267) and Moxifloxacin (21.3%), N=57/267], were found to be high within a global context. Comparing rates of drug resistance among lineages, and exploring the dynamics of resistance acquisition through time, suggest the Beijing lineage (lineage 2.2) acquiresde novoresistance mutations at higher rates and suffers no apparent fitness cost acting to impede the transmission of resistance. We infer resistance to INH and STR to have arisen earlier, on average, than resistance to RIF, and to be more widespread across the phylogeny. The high prevalence of ‘background’ INH resistance, combined with high rates of RIF mono-resistance (20.7%, N=18/87) suggests that rapid assays for INH resistance will be valuable in this setting. These tests will allow the detection of INH mono-resistance, and will allow MDR isolates to be distinguished from isolates with RIF mono-resistance.

Genomic researchers are increasingly utilizing commercial cloud platforms (CCPs) to manage their data and analytics needs. Commercial clouds allow researchers to grow their storage and analytics capacity on demand, keeping pace with expanding project data footprints and enabling researchers to avoid large capital expenditures while paying only for IT capacity consumed by their project. Cloud computing also allows researchers to overcome common network and storage bottlenecks encountered when combining or re-analysing large datasets. However, cloud computing presents a new set of challenges. Without adequate security controls, the risk of unauthorised access may be higher for data stored on the cloud. In addition, regulators are increasingly mandating data access patterns and specific security protocols on the storage and use of genomic data to safeguard rights of the study participants. While CCPs provide tools for security and regulatory compliance, utilising these tools to build the necessary controls required for cloud solutions is not trivial as such skill sets are not commonly found in a genomics lab. The Research Assets Provisioning and Tracking Online Repository (RAPTOR) by the Genome Institute of Singapore is a cloud native genomics data repository and analytics platform focusing on security and regulatory compliance. Using a “five-safes” framework (Safe Purpose, Safe People, Safe Settings, Safe Data and Safe Output), RAPTOR provides security and governance controls to data contributors and users leveraging cloud computing for sharing and analysis of large genomic datasets without the risk of security breaches or running afoul of regulations. RAPTOR can also enable data federation with other genomic data repositories using GA4GH community-defined standards, allowing researchers to boost the statistical power of their work and overcome geographic and ancestry limitations of data sets

Background:To evaluate the utility of polygenic risk scores (PRSs) in identifying high-risk individuals, different publicly available PRSs for breast (n=85), prostate (n=37), colorectal (n=22), and lung cancers (n=11) were examined in a prospective study of 21,694 Chinese adults.Methods:We constructed PRS using weights curated in the online PGS Catalog. PRS performance was evaluated by distribution, discrimination, predictive ability, and calibration. Hazard ratios (HR) and corresponding confidence intervals (CI) of the common cancers after 20 years of follow-up were estimated using Cox proportional hazard models for different levels of PRS.Results:A total of 495 breast, 308 prostate, 332 female-colorectal, 409 male-colorectal, 181 female-lung, and 381 male-lung incident cancers were identified. The area under receiver operating characteristic curve for the best-performing site-specific PRS were 0.61 (PGS000873, breast), 0.70 (PGS00662, prostate), 0.65 (PGS000055, female-colorectal), 0.60 (PGS000734, male-colorectal), 0.56 (PGS000721, female-lung), and 0.58 (PGS000070, male-lung), respectively. Compared to the middle quintile, individuals in the highest cancer-specific PRS quintile were 64% more likely to develop cancers of the breast, prostate, and colorectal. For lung cancer, the lowest cancer-specific PRS quintile was associated with 28–34% decreased risk compared to the middle quintile. In contrast, the HR observed for quintiles 4 (female-lung: 0.95 [0.61–1.47]; male-lung: 1.14 [0.82–1.57]) and 5 (female-lung: 0.95 [0.61–1.47]) were not significantly different from that for the middle quintile.Conclusions:Site-specific PRSs can stratify the risk of developing breast, prostate, and colorectal cancers in this East Asian population. Appropriate correction factors may be required to improve calibration.Funding:This work is supported by the National Research Foundation Singapore (NRF-NRFF2017-02), PRECISION Health Research, Singapore (PRECISE) and the Agency for Science, Technology and Research (A*STAR). WP Koh was supported by National Medical Research Council, Singapore (NMRC/CSA/0055/2013). CC Khor was supported by National Research Foundation Singapore (NRF-NRFI2018-01). Rajkumar Dorajoo received a grant from the Agency for Science, Technology and Research Career Development Award (A*STAR CDA - 202D8090), and from Ministry of Health Healthy Longevity Catalyst Award (HLCA20Jan-0022).The Singapore Chinese Health Study was supported by grants from the National Medical Research Council, Singapore (NMRC/CIRG/1456/2016) and the U.S. National Institutes of Health (NIH) (R01 CA144034 and UM1 CA182876).

Glaucomatous optic nerve damage is caused by selective death of retinal ganglion cells (RGCs). Another condition with underlying loss of RGCs is autosomal dominant optic atrophy (ADOA). Majority of...

Background Skeletal dysplasia is a heterogeneous group of disorders. Spondyloepiphyseal dysplasias comprise one subgroup. Deficiency of carbohydrate sulfotransferase 3 has been reported in a small number of patients with recessively inherited spondyloepiphyseal dysplasia with joint dislocation, short stature and scoliosis. We report here molecular and clinical findings of affected individuals in three consanguineous Pakistani families. Affected individuals in all three families had a uniform phenotype including severe short stature, multiple dislocated joints, progressive scoliosis and facial dysmorphism. Methods Clinical evaluation was done for three unrelated families. Radiological survey of bones was completed for patients from two of the families. Whole exome sequencing index patients from each family was performed followed by Sanger sequencing for validation of segregation of identified variants in respective families. In-silico analysis for determining pathogenicity of identified variants and conservation was done. Results Whole-exome sequencing revealed biallelic variants c.590 T > C;p.(Leu197Pro), c.603C > A;p.(Tyr201Ter) and c.661C > T;p.(Arg221Cys) in CHST3 (NM_004273.5) in the three families with eight, five and two affected individuals, respectively. Contrary to previous reports, affected individuals in none of the families exhibited a hearing loss. Conclusion We describe genotypic and phenotypic findings of three unrelated families with spondyloepiphyseal dysplasia. Our study confirms phenotypic variability and adds to the genotypic spectrum of spondyloepiphyseal dysplasia.

Background Early-life interpersonal stress, particularly childhood maltreatment, is associated with neurobiological abnormalities. However, few studies have investigated the neural effects of peer victimisation. Aims This study examines common and specific associations between childhood maltreatment, peer victimisation and brain structural alterations in youths. Method Grey matter volume (GMV) and cortical thickness data were collected from 105 age- and gender-matched youths (age range: 17–21 years). Region-of-interest and whole-brain analyses were conducted. Results For the region-of-interest analyses, the childhood maltreatment group had smaller GMV than controls in left inferior frontal gyrus, bilateral anterior insula, postcentral and lingual regions, which were associated with greater emotional abuse, along with smaller insular GMV than the peer victimisation group, who had smaller left lingual and postcentral GMV than controls. At the whole-brain level, both childhood maltreatment and peer victimisation groups had smaller GMV than controls in a cluster comprising left post/precentral, inferior frontal gyrus, insula, superior parietal and supramarginal gyri. The peer victimisation group alone had increased cortical thickness in a cluster comprising left superior frontal, anterior cingulate and medial orbitofrontal gyri, which was related to greater cyberbullying. Conclusions Early-life interpersonal stress is associated with common structural alterations of the inferior frontal-limbic, sensory and lingual regions involved in cognitive control, emotion and sensory processing. The findings of childhood-maltreatment-related reduced anterior insular GMV and peer-victimisation-related increased cortical thickness in the left medial prefrontal-anterior cingulate cluster underscore the distinctive negative effects of childhood maltreatment and peer victimisation, and suggest that peer victimisation, particularly cyberbullying, could be as detrimental as childhood maltreatment.

To investigate whether recently identified genetic loci for primary angle-closure glaucoma (PACG) are associated with disease severity.Case-control study.Eight hundred four PACG patients and 943 control participants of Chinese ethnicity from Singapore.The 8 PACG-associated single nucleotide polymorphisms (SNPs; rs11024102 at PLEKHA7, rs3753841 at COL11A1, rs1015213 located between PCMTD1 and ST18 on chromosome 8q, rs3816415 at EPDR1, rs1258267 at CHAT, rs736893 at GLIS3, rs7494379 at FERMT2, and rs3739821 mapping in between DPM2 and FAM102A) identified from genome-wide association studies were tested for association with disease severity using logistic regression adjusted for age and gender. A P value of 0.006 was set as significant after Bonferroni correction for testing of 8 loci. We also calculated the weighted genetic risk score (GRS) weighted by the estimated individual SNP effect size on PACG calculated as logarithm of the odds ratio (OR). Disease severity was based on the visual field mean deviation (MD) and classified as early to moderate (MD,-12 dB) and severe (MD,-20 dB).Association of PACG loci with severe disease.Of the 804 PACG patients, genotyping data were available for 768 individuals and included 436 with mild-to-moderate PACG and 206 with severe PACG. The PACG patients were significantly older (mean age, 64.3 ± 9.1 years vs. 56.4 ± 8.9 years; P0.001) and there were proportionately more women compared with control participants (58.4% vs. 49.0%; P0.001). Of the 8 loci investigated, we observed significant evidence of association with severe PACG at 1 SNP, namely rs3816415 in EPDR1 (OR, 2.03; 95% confidence interval [CI], 1.49-2.78; P = 1 × 10Our results show that EPDR1 is associated significantly with severe PACG, suggesting that it may predispose patients to more aggressive disease development. Individuals with PACG with a higher GRS were associated with a higher risk of severe PACG.

Purpose of review The genetic basis of pseudoexfoliation (PEX) syndrome, the most common identifiable cause of open-angle glaucoma, is steadily being elucidated. This review summarizes the recent advances on genetic risk factors for PEX syndrome/glaucoma and their potential functional implications in PEX pathophysiology. Recent findings As of today, seven loci associated with the risk of PEX surpassing genome-wide significance have been identified by well-powered genome-wide association studies and sequencing efforts. LOXL1 (lysyl oxidase-like 1) represents the major genetic effect locus, although the biological role of common risk variants and their reversed effect in different ethnicities remain an unresolved problem. Rare protein-coding variants at LOXL1 and a single noncoding variant downstream of LOXL1 showed no allele effect reversal and suggested potential roles for elastin homeostasis and vitamin A metabolism in PEX pathogenesis. Other PEX-associated genetic variants provided biological insights into additional disease processes and pathways, including ubiquitin-proteasome function, calcium signaling, and lipid biosynthesis. Gene-environment interactions, epigenetic alterations, and integration of multiomics data have further contributed to our knowledge of the complex etiology underlying PEX syndrome and glaucoma. Summary PEX-associated genes are beginning to reveal relevant biological pathways and processes involved in disease development. To understand the functional consequences and molecular mechanisms of these loci and to translate them into novel therapeutic approaches are the major challenges for the future.

Nuclear cataract is the most common type of age-related cataract and a leading cause of blindness worldwide. Age-related nuclear cataract is heritable (h2 = 0.48), but little is known about specific genetic factors underlying this condition. Here we report findings from the largest to date multi-ethnic meta-analysis of genome-wide association studies (discovery cohort N = 14,151 and replication N = 5299) of the International Cataract Genetics Consortium. We confirmed the known genetic association of CRYAA (rs7278468, P = 2.8 × 10−16) with nuclear cataract and identified five new loci associated with this disease: SOX2-OT (rs9842371, P = 1.7 × 10−19), TMPRSS5 (rs4936279, P = 2.5 × 10−10), LINC01412 (rs16823886, P = 1.3 × 10−9), GLTSCR1 (rs1005911, P = 9.8 × 10−9), and COMMD1 (rs62149908, P = 1.2 × 10−8). The results suggest a strong link of age-related nuclear cataract with congenital cataract and eye development genes, and the importance of common genetic variants in maintaining crystalline lens integrity in the aging eye., Here, the authors report a multi-ethnic genome wide association meta-analysis of 12 studies from the International Cataract Genetics Consortium. They find six new loci associated with age-related nuclear cataract, in addition to replicating the association at CRYAA, and suggest a strong genetic link between age-related nuclear and congenital cataracts.

Background Telomere attrition has been proposed as a hallmark of aging. We previously reported on the association between blood leukocyte telomere length (LTL) at midlife and risk of chronic diseases and mortality. Methods In this study, we investigated the effect of midlife LTL and genetic proxies on 5 markers of aging outcomes, namely handgrip strength, timed up-and-go (TUG), Singapore-modified Mini-Mental State Examination (SM-MMSE) scores, anxiety, and depression indices, measured after a median 20-year follow-up in the Singapore Chinese Health Study (N = 9581). Results We observed a significant association between midlife LTL and handgrip strength later in life (p = .004, padjust = .020), as well as a nominal significant association between midlife LTL and TUG later in life (p = .036, padjust = .180). The weighted Genetic Risk Score (wGRS) comprising 15 previously reported LTL reducing loci in East Asians was not significantly associated with handgrip strength. However, results from Structural Equation Modeling showed that the effect of this wGRS on handgrip strength was mediated through LTL (proportion of wGRS effect on handgrip strength mediated through LTL = 33.3%, p = .010). Conclusions Longer midlife LTL was associated with increased handgrip strength later in life.

Supplemental Digital Content is available in the text., Background: To assess the genetic architecture of hypertrophic cardiomyopathy (HCM) in patients of predominantly Chinese ancestry. Methods: We sequenced HCM disease genes in Singaporean patients (n=224) and Singaporean controls (n=3634), compared findings with additional populations and White HCM cohorts (n=6179), and performed in vitro functional studies. Results: Singaporean HCM patients had significantly fewer confidently interpreted HCM disease variants (pathogenic/likely pathogenic: 18%, P

Background Shorter telomere length (TL) has been associated with poor health behaviors, increased risks of chronic diseases and early mortality. Excessive shortening of telomere is a marker of accelerated aging and can be influenced by oxidative stress and nutritional deficiency. Plasma n6:n3 polyunsaturated fatty acid (PUFA) ratio may impact cell aging. Increased dietary intake of marine n-3 PUFA is associated with reduced telomere attrition. However, the effect of plasma PUFA on leukocyte telomere length (LTL) and its interaction with genetic variants are not well established. Methods A nested coronary artery disease (CAD) case-control study comprising 711 cases and 638 controls was conducted within the Singapore Chinese Health Study (SCHS). Samples genotyped with the Illumina ZhongHua-8 array. Plasma n-3 and n-6 PUFA were quantified using mass spectrometry (MS). LTL was measured with quantitative PCR method. Linear regression was used to test the association between PUFA and LTL. The interaction between plasma PUFAs and genetic variants was assessed by introducing an additional term (PUFA×genetic variant) in the regression model. Analysis was carried out in cases and controls separately and subsequently meta-analyzed using the inverse-variance weighted method. We further assessed the association of PUFA and LTL with CAD risk by Cox Proportional-Hazards model and whether the effect of PUFA on CAD was mediated through LTL by using structural equation modeling. Results Higher n6:n3 ratio was significantly associated with shorter LTL (p = 0.018) and increased CAD risk (p = 0.005). These associations were mainly driven by elevated plasma total n-3 PUFAs, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (p p − 8). Mediation analysis showed that PUFA and LTL affected CAD risk independently. Conclusions Higher plasma n6:n3 PUFA ratio, and lower EPA and DHA n-3 PUFAs were associated with shorter LTL and increased CAD risk in this Chinese population. Furthermore, genetic variants may modify the effect of PUFAs on LTL. PUFA and LTL had independent effect on CAD risk in our study population.

Keratoconus is a common ocular disorder that causes progressive corneal thinning and is the leading indication for corneal transplantation. Central corneal thickness (CCT) is a highly heritable characteristic that is associated with keratoconus. In this two-stage genome-wide association study (GWAS) of CCT, we identified a locus for CCT, namely STON2 rs2371597 (P = 2.32 × 10−13), and confirmed a significant association between STON2 rs2371597 and keratoconus development (P = 0.041). Additionally, strong STON2 expression was observed in mouse corneal epithelial basal cells. We also identified SMAD3 rs12913547 as a susceptibility locus for keratoconus development using predictive analysis with IBM’s Watson question answering computer system (P = 0.001). Further GWAS analyses combined with Watson could effectively reveal detailed pathways underlying keratoconus development., Yoshikatsu Hosoda et al. study the genetic basis for central corneal thickness (CCT) that is associated with keratoconus. They identify two susceptibility loci, STON2 rs2371597 and SMAD3 rs12913547, using two-step genome-wide association study (GWAS) and predictive analysis with IBM’s Watson question answering computer system, respectively.

The major human genes regulating Mycobacterium tuberculosis–induced immune responses and tuberculosis (TB) susceptibility are poorly understood. Although IL-12 and IL-10 are critical for TB pathogenesis, the genetic factors that regulate their expression in humans are unknown. CNBP, REL, and BHLHE40 are master regulators of IL-12 and IL-10 signaling. We hypothesized that common variants in CNBP, REL, and BHLHE40 were associated with IL-12 and IL-10 production from dendritic cells, and that these variants also influence adaptive immune responses to bacillus Calmette–Guérin (BCG) vaccination and TB susceptibility. We characterized the association between common variants in CNBP, REL, and BHLHE40, innate immune responses in dendritic cells and monocyte-derived macrophages, BCG-specific T cell responses, and susceptibility to pediatric and adult TB in human populations. BHLHE40 single-nucleotide polymorphism (SNP) rs4496464 was associated with increased BHLHE40 expression in monocyte-derived macrophages and increased IL-10 from peripheral blood dendritic cells and monocyte-derived macrophages after LPS and TB whole-cell lysate stimulation. SNP BHLHE40 rs11130215, in linkage disequilibrium with rs4496464, was associated with increased BCG-specific IL-2+CD4+ T cell responses and decreased risk for pediatric TB in South Africa. SNPs REL rs842634 and rs842618 were associated with increased IL-12 production from dendritic cells, and SNP REL rs842618 was associated with increased risk for TB meningitis. In summary, we found that genetic variations in REL and BHLHE40 are associated with IL-12 and IL-10 cytokine responses and TB clinical outcomes. Common human genetic regulation of well-defined intermediate cellular traits provides insights into mechanisms of TB pathogenesis.

Glaucoma, a diverse group of eye disorders that results in the degeneration of retinal ganglion cells, is the world's leading cause of irreversible blindness. Apart from age and ancestry, the major risk factor for glaucoma is increased intraocular pressure (IOP). In primary open-angle glaucoma (POAG), the anterior chamber angle is open but there is resistance to aqueous outflow. In primary angle-closure glaucoma (PACG), crowding of the anterior chamber angle due to anatomical alterations impede aqueous drainage through the angle. In exfoliation syndrome and exfoliation glaucoma, deposition of white flaky material throughout the anterior chamber directly interfere with aqueous outflow. Observational studies have established that there is a strong hereditable component for glaucoma onset and progression. Indeed, a succession of genome wide association studies (GWAS) that were centered upon single nucleotide polymorphisms (SNP) have yielded more than a hundred genetic markers associated with glaucoma risk. However, a shortcoming of GWAS studies is the difficulty in identifying the actual effector genes responsible for disease pathogenesis. Building on the foundation laid by GWAS studies, research groups have recently begun to perform whole exome-sequencing to evaluate the contribution of protein-changing, coding sequence genetic variants to glaucoma risk. The adoption of this technology in both large population-based studies as well as family studies are revealing the presence of novel, protein-changing genetic variants that could enrich our understanding of the pathogenesis of glaucoma. This review will cover recent advances in the genetics of primary open-angle glaucoma, primary angle-closure glaucoma and exfoliation glaucoma, which collectively make up the vast majority of all glaucoma cases in the world today. We will discuss how recent advances in research methodology have uncovered new risk genes, and how follow up biological investigations could be undertaken in order to define how the risk encoded by a genetic sequence variant comes into play in patients. We will also hypothesise how data arising from characterising these genetic variants could be utilized to predict glaucoma risk and the manner in which new therapeutic strategies might be informed.

International audience; No abstract available

Background Family history, and genetic and non-genetic risk factors can stratify women according to their individual risk of developing breast cancer. The extent of overlap between these risk predictors is not clear. Methods In this case-only analysis involving 7600 Asian breast cancer patients diagnosed between age 30 and 75 years, we examined identification of high-risk patients based on positive family history, the Gail model 5-year absolute risk [5yAR] above 1.3%, breast cancer predisposition genes (protein-truncating variants [PTV] in ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, or TP53), and polygenic risk score (PRS) 5yAR above 1.3%. Results Correlation between 5yAR (at age of diagnosis) predicted by PRS and the Gail model was low (r=0.27). Fifty-three percent of breast cancer patients (n=4041) were considered high risk by one or more classification criteria. Positive family history, PTV carriership, PRS, or the Gail model identified 1247 (16%), 385 (5%), 2774 (36%), and 1592 (21%) patients who were considered at high risk, respectively. In a subset of 3227 women aged below 50 years, the four models studied identified 470 (15%), 213 (7%), 769 (24%), and 325 (10%) unique patients who were considered at high risk, respectively. For younger women, PRS and PTVs together identified 745 (59% of 1276) high-risk individuals who were not identified by the Gail model or family history. Conclusions Family history and genetic and non-genetic risk stratification tools have the potential to complement one another to identify women at high risk.

Carriers of functionally deficient mutations in the CYP39A1 gene have been recently reported to have a 2-fold increased risk of exfoliation syndrome (XFS). The aim of this study was to evaluate the risk of blindness and related clinical phenotypes of XFS patients carrying the loss-of-function CYP39A1 G204E mutation in comparison with XFS patients without any CYP39A1 mutation.Retrospective case study.A total of 35 patients diagnosed with XFS carrying the CYP39A1 G204E mutation and 150 XFS patients without any CYP39A1 mutation who were randomly selected from the Japanese XFS cohort.Two-sided Fisher exact test with an alpha level0.05 was used to estimate the significance of the calculated odds ratio (OR) for all categorical measures. Comparisons between groups of subjects were performed using linear mixed effect models with group as random effect and taking possible dependence between eyes within a subject into account.Primary analysis compared the incidence of blindness (defined as visual acuity [VA]0.05 decimal), prevalence of exfoliation glaucoma (XFG), history of glaucoma surgery, and indices of glaucoma severity such as visual field (VF) mean deviation (MD), intraocular pressure (IOP), and vertical cup-disc ratio (CDR) between CYP39A1 G204E carriers and those without any CYP39A1 mutation.The overall risk for blindness was significantly higher in XFS patients carrying the CYP39A1 G204E variant (10/35 [28.6%]) compared with XFS patients without any CYP39A1 mutations (8/150 [5.4%]; odds ratio [OR], 7.1; 95% confidence interval [CI], 2.7-20.2]; P0.001). A higher proportion of XFS patients with the CYP39A1 G204E mutation (23/35 [65.7%]) had evidence of XFG in at least 1 eye compared with the comparison group (41/150 [27.3%]; OR, 5.1; 95% CI, 2.4-11.4]; P0.0001). Significantly higher peak IOP, larger vertical CDR, and worse VF MD were also found in CYP39A1 G204E variant carriers (P0.001). Additionally, patients with the CYP39A1 G204E mutation (18/35 [51.4%]) required more laser or glaucoma surgical interventions compared with those without any CYP39A1 mutation (32/150 [21.3%], P0.001).Patients with XFS carrying the CYP39A1 G204E mutation had significantly increased risk of blindness, higher occurrence of XFG, and more severe glaucoma compared with patients with XFS without any CYP39A1 mutation.

Glaucomatous optic nerve damage is caused by selective death of retinal ganglion cells (RGCs). Another condition with underlying loss of RGCs is autosomal dominant optic atrophy (ADOA). Majority of ADOA patients have mutations inFourThere was a significant difference in genotype frequencies of rs9851685 and rs2111534 polymorphisms between glaucoma patients and control subjects. Several genotype combinations comprising SNPs atIn studied population, genotype CC and allele C of rs9851685

Background Ethnic-specific genetic risk assessment framework for Parkinson's disease (PD) is lacking for the Asian population. Objective We investigated the association of a polygenic risk score (PRS) with PD incidence in a population-based Asian prospective cohort. Methods Genetic, dietary, and lifestyle information were prospectively collected from 25,646 participants within the Singapore Chinese Health Study cohort. PRS was constructed with Asian-specific and top genome-wide association study variants. The association between PRS and PD incidence was evaluated with multivariable Cox proportional hazard models, Kaplan-Meier survival analysis, and concordance statistics. Results A total of 333 incident cases were identified after a follow-up period of more than 20 years. Participants with PRS in the top tertile (hazard ratio [HR], 1.81; 95% confidence interval [CI], 1.37-2.39) and middle tertile (HR, 1.35; 95% CI, 1.00-1.83) are at higher risk of developing PD after adjusting for dietary and lifestyle risk factors, with a shorter time to PD event in a Kaplan-Meier survival analysis (P Conclusion We identified a PRS that was significantly associated with PD incidence in a prospective Chinese cohort after adjusting for dietary and lifestyle factors. © 2021 International Parkinson and Movement Disorder Society.

PurposeCommon LOXL1 protein-altering variants are significant genetic risk factors for exfoliation syndrome (XFS) and the related secondary glaucoma (XFG). A rare LOXL1 missense allele has been associated with protective effects in a Japanese cohort, suggesting that other rare alleles may also exhibit protective effects. The goal of this study was to assess the contributions of rare LOXL1 variants to XFS/XFG risk in cases and controls from the United States.MethodsLOXL1 rare (minor allele frequency less than 1%) variants were identified from Humanexome BeadArray (Illumina) data for 1118 XFS/XFG cases and 3661 controls. Distribution of rare variants, haplotypes (defined using IMPUTE2) and diplotypes were examined using the Fisher’s exact test. Rare variant allele distribution was confirmed in an independent set of primary open angle glaucoma (POAG) controls and multi-ethnic datasets. Correlation of LOXL1 common allele homozygosity with disease risk used data from gnomAD (gnomad.broadinstitute.org/) and an existing multi-ethnic meta-analysis.ResultsFour rare LOXL1 missense alleles were identified, and all were more common in controls (combined P= 7.6E-4), with two of these located in a LOXL1 intrinsic disordered region (IDR) known to be involved in LOXL1 aggregation. Haplotypes that included the rare or minor variants were more common in controls compared to cases (OR= 0.33, P=1.7E-8). Heterozygous diplotypes were significantly associated with reduced risk overall (OR= 0.45 P= 1.7 E-89) with the largest effects observed for diplotypes with more than one heterozygous genotype (OR= 0.05, P= 1.0E-39). A homozygous diplotype was associated with increased disease risk (OR= 6.8, P= 4.7E-157) and homozygosity was correlated with disease risk for common LOXL1 variants across multi-ethnic populations (Pearson= 0.92, PConclusionsUsing exome array data from XFS/XFG cases and controls from the United States, we identify 4 rare protective LOXL1 missense variants and show that the distribution of the corresponding haplotypes and diplotypes are associated with reduced risk of XFS/XFG. The diplotype results also demonstrate that LOXL1 allelic heterozygosity is protective while homozygosity is associated with increased disease risk. These results suggest that LOXL1 minor allele frequency variation among populations, with corresponding variation in genotype heterozgyosity and homozygosity, determines the XFS/XFG association effects and that genotypic effects may also impact protein aggregation involving intrinsic disordered regions.

The genetic basis of overall healthy ageing, especially among the East-Asian population is understudied. We conducted a genome-wide association study among 1618 Singapore Chinese elderly participants (65 years or older) ascertained to have aged healthily and compared their genome-wide genotypes to 6221 participants who did not age healthily, after a 20-year follow-up. Two genetic variants were identified (PMeta −8) to be associated with healthy aging, including the LRP1B locus previously associated in long-lived individuals without cognitive decline. Our study sheds additional insights on the genetic basis of healthy ageing.

Context Kallmann syndrome (KS) is a rare, genetically heterogeneous Mendelian disorder. Structural defects in KS patients have helped define the genetic architecture of gonadotropin-releasing hormone (GnRH) neuronal development in this condition. Objective Examine the functional role a novel structural defect affecting a long noncoding RNA (lncRNA), RMST, found in a KS patient. Design Whole genome sequencing, induced pluripotent stem cells and derived neural crest cells (NCC) from the KS patient were contrasted with controls. Setting The Harvard Reproductive Sciences Center, Massachusetts General Hospital Center for Genomic Medicine, and Singapore Genome Institute. Patient A KS patient with a unique translocation, t(7;12)(q22;q24). Interventions/Main Outcome Measure/Results A novel translocation was detected affecting the lncRNA, RMST, on chromosome 12 in the absence of any other KS mutations. Compared with controls, the patient’s induced pluripotent stem cells and NCC provided functional information regarding RMST. Whereas RMST expression increased during NCC differentiation in controls, it was substantially reduced in the KS patient’s NCC coincident with abrogated NCC morphological development and abnormal expression of several “downstream” genes essential for GnRH ontogeny (SOX2, PAX3, CHD7, TUBB3, and MKRN3). Additionally, an intronic single nucleotide polymorphism in RMST was significantly implicated in a genome-wide association study associated with age of menarche. Conclusions A novel deletion in RMST implicates the loss of function of a lncRNA as a unique cause of KS and suggests it plays a critical role in the ontogeny of GnRH neurons and puberty.

Purpose: The aim of this study was to evaluate the frequency of single nucleotide polymorphisms (SNP) of estrogen receptor genes (ESR1: rs12154178, rs1884054 and ESR2: rs1268656, rs7159462)...

Genetic factors underlying leukocyte telomere length (LTL) may provide insights into telomere homeostasis, with direct links to disease susceptibility. Genetic evaluation of 23,096 Singaporean Chinese samples identifies 10 genome-wide loci (P, Shortening of leukocyte telomere length (LTL) is associated with age and increased risk for various chronic diseases. Here, the authors report genome-wide association studies for LTL in Singaporean Chinese populations and find that longer LTL associates with less severe outcomes of respiratory disease phenotypes.

© The Author(s) 2019. A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-Alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2- degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10?6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10?8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models. National Heart, Lung, and Blood Institute; American Heart Association Grant

Importance: Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders.Objectives: To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma.Design, Settings, and Participants: A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma.Exposures: Genetic variants associated with primary open-angle glaucoma.Main Outcomes and Measures: Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10−8 in the discovery stage and in the meta-analysis of combined discovery and validation data.Results: A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10−8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10−13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry.Conclusions and Relevance: In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies.

The current understanding of genetic susceptibility factors for nasopharyngeal carcinoma (NPC) is still incomplete. To identify novel germline variants associated with NPC predisposition, we analysed whole-exome sequencing data from 119 NPC patients from Singapore with a family history of NPC and/or with early-onset NPC, together with 1337 Singaporean participants without NPC. Variants were prioritised and filtered by selecting variants with minor allele frequencies of 20). Using single-variant testing, we identified 17 rare pathogenic variants in 17 genes that were associated with NPC. Consistent evidence of enrichment in NPC patients was observed for five of these variants (in JAK2, PRDM16, LRP1B, NIN, and NKX2-1) from an independent case-control comparison of 156 NPC patients and 9770 unaffected individuals. In a family with five siblings, a FANCE variant (p. P445S) was detected in two affected members, but not in three unaffected members. Gene-based burden testing recapitulated variants in NKX2-1 and FANCE as being associated with NPC risk. Using pathway analysis, endocytosis and immune-modulating pathways were found to be enriched for mutation burden. This study has identified NPC-predisposing variants and genes which could shed new insights into the genetic predisposition of NPC.

Purpose: It is difficult to identify people with non-alcoholic fatty liver disease (NAFLD) who are at high risk for the development of hepatocellular carcinoma (HCC). A polygenic risk score (PRS) for hepatic fat derived from non-Asians has been reported to be associated with HCC risk in European populations. However, population level data of this risk in non-European populations are lacking. Methods: Utilizing resources from the Singapore Chinese Health Study (SCHS), we examined the relationship between the previously published hepatic fat PRS (HFC-PRS) and HCC risk. We also constructed and evaluated a NAFLD-related PRS (NAFLD-PRS); the final version included SNPs in similar gene regions as the HFC-PRS but weighted by effect estimates for NAFLD among those with East Asian ancestry. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) of HCC incidence with both HFC-PRS and NAFLD-PRS. Results: The HFC-PRS and NAFLD-PRS were highly correlated (Spearman r = 0.79, P < 0.001). The highest quartiles of both the HFC-PRS and the NAFLD-PRS were associated with significantly increased risk of HCC with HR of 2.39 (95% CI 1.51, 3.78) and 1.77 (95% CI 1.15, 2.73), respectively, compared to their respective lowest quartile. Conclusion: The HFC-PRS and the NAFLD-PRS may both be useful in stratifying Asian populations according to their risk of HCC. In addition, the association between the NAFLD-PRS, derived from East Asians, and HCC risk suggests a potential causal role for NAFLD in the development of HCC in this population. Citation Format: Claire E. Thomas, Brenda Diergaarde, Allison L. Kuipers, Jennifer J. Adibi, Hung N. Luu, Xuling Chang, Rajkumar Dorajoo, Chew-Kiat Heng, Chiea-Chuen Khor, Renwei Wang, Aizhen Jin, Woon-Puay Koh, Jian-Min Yuan. Non-alcoholic fatty liver disease polygenic risk score and risk of hepatocellular carcinoma in an East Asian population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2260.