Publications by authors named "Xueling Sim"

137 Publications

Association of leukocyte telomere length with chronic kidney disease in East Asians with type 2 diabetes: a Mendelian randomization study.

Clin Kidney J 2021 Nov 26;14(11):2371-2376. Epub 2021 Mar 26.

Clinical Research Unit, Khoo Teck Puat Hospital, Singapore.

Background: Chronic kidney disease (CKD) is common among people with type 2 diabetes (T2D), and increases the risk of kidney failure and cardiovascular diseases. Shorter leukocyte telomere length (LTL) is associated with CKD in patients with T2D. We previously reported single-nucleotide polymorphisms (SNPs) associated with LTL in an Asian population. In this study, we elucidated the association of these SNPs with CKD in patients with T2D using the Mendelian randomization (MR) approach.

Methods: The cross-sectional association of 16 LTL SNPs with CKD, defined as an estimated glomerular filtration rate of <60 mL/min/1.73 m, was assessed among 4768 (1628 cases and 3140 controls) participants in the Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in T2D and Diabetic Nephropathy cohorts. MR analysis was performed using the random-effect inverse-variance weighted (IVW) method, the weighted median, MR-Egger and Radial MR adjusted for age and sex-stratified by cohorts and ethnicity (Chinese and Malays), then meta-analyzed.

Results: Genetically determined shorter LTL was associated with increased risk of CKD in patients with T2D (meta-IVW adjusted odds ratio= 1.51, 95% confidence interval 1.12-2.12, P=0.007, P =0.547). Similar results were obtained following sensitivity analysis. MR-Egger analysis (intercept) suggested no evidence of horizontal pleiotropy (= 0.010, P=0.751).

Conclusions: Our findings suggest that genetically determined LTL is associated with CKD in patients with T2D. Further studies are warranted to elucidate the causal role of telomere length in CKD progression.
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http://dx.doi.org/10.1093/ckj/sfab067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8573005PMC
November 2021

Multi-Ancestry Genome-wide Association Study Accounting for Gene-Psychosocial Factor Interactions Identifies Novel Loci for Blood Pressure Traits.

HGG Adv 2021 Jan 31;2(1). Epub 2020 Oct 31.

Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, 17489, Germany.

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (), synaptic function and neurotransmission (), as well as genes previously implicated in neuropsychiatric or stress-related disorders (). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.
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http://dx.doi.org/10.1016/j.xhgg.2020.100013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8562625PMC
January 2021

Impact of BMI and waist circumference on epigenome-wide DNA methylation and identification of epigenetic biomarkers in blood: an EWAS in multi-ethnic Asian individuals.

Clin Epigenetics 2021 10 20;13(1):195. Epub 2021 Oct 20.

Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, 12 Science Drive 2, #10-01, Tahir Foundation Building, Singapore, 117549, Singapore.

Background: The prevalence of obesity and its related chronic diseases have been increasing especially in Asian countries. Obesity-related genetic variants have been identified, but these explain little of the variation in BMI. Recent studies reported associations between DNA methylation and obesity, mostly in non-Asian populations.

Methods: We performed an epigenome-wide association study (EWAS) on general adiposity (body mass index, BMI) and abdominal adiposity (waist circumference, WC) in 409 multi-ethnic Asian individuals and replicated BMI and waist-associated DNA methylation CpGs identified in other populations. The cross-lagged panel model and Mendelian randomization were used to assess the temporal relationship between methylation and BMI. The temporal relationship between the identified CpGs and inflammation and metabolic markers was also examined.

Results: EWAS identified 116 DNA methylation CpGs independently associated with BMI and eight independently associated with WC at false discovery rate P < 0.05 in 409 Asian samples. We replicated 110 BMI-associated CpGs previously reported in Europeans and identified six novel BMI-associated CpGs and two novel WC-associated CpGs. We observed high consistency in association direction of effect compared to studies in other populations. Causal relationship analyses indicated that BMI was more likely to be the cause of DNA methylation alteration, rather than the consequence. The causal analyses using BMI-associated methylation risk score also suggested that higher levels of the inflammation marker IL-6 were likely the consequence of methylation change.

Conclusion: Our study provides evidence of an association between obesity and DNA methylation in multi-ethnic Asians and suggests that obesity can drive methylation change. The results also suggested possible causal influence that obesity-related methylation changes might have on inflammation and lipoprotein levels.
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http://dx.doi.org/10.1186/s13148-021-01162-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8527674PMC
October 2021

Genetic discovery and risk characterization in type 2 diabetes across diverse populations.

HGG Adv 2021 Apr 9;2(2). Epub 2021 Mar 9.

Division of Statistical Genomics, School of Medicine, Washington University, St. Louis, MO, USA.

Genomic discovery and characterization of risk loci for type 2 diabetes (T2D) have been conducted primarily in individuals of European ancestry. We conducted a multiethnic genome-wide association study of T2D among 53,102 cases and 193,679 control subjects from African, Hispanic, Asian, Native Hawaiian, and European population groups in the Population Architecture Genomics and Epidemiology (PAGE) and Diabetes Genetics Replication and Meta-analysis (DIAGRAM) Consortia. In individuals of African ancestry, we discovered a risk variant in the gene (rs11466334, risk allele frequency (RAF) = 6.8%, odds ratio [OR] = 1.27, p = 2.06 × 10), which replicated in independent studies of African ancestry (p = 6.26 × 10). We identified a multiethnic risk variant in the gene (rs13052926, RAF = 14.1%, OR = 1.08, p = 5.75 × 10), which also replicated in independent studies (p = 3.45 × 10). We also observed a significant difference in the performance of a multiethnic genetic risk score (GRS) across population groups (p = 3.85 × 10). Comparing individuals in the top GRS risk category (40%-60%), the OR was highest in Asians (OR = 3.08) and European (OR = 2.94) ancestry populations, followed by Hispanic (OR = 2.39), Native Hawaiian (OR = 2.02), and African ancestry (OR = 1.57) populations. These findings underscore the importance of genetic discovery and risk characterization in diverse populations and the urgent need to further increase representation of non-European ancestry individuals in genetics research to improve genetic-based risk prediction across populations.
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http://dx.doi.org/10.1016/j.xhgg.2021.100029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486151PMC
April 2021

APOC3 genetic variation, serum triglycerides, and risk of coronary artery disease in Asian Indians, Europeans, and other ethnic groups.

Lipids Health Dis 2021 Sep 21;20(1):113. Epub 2021 Sep 21.

Duke-NUS Medical School, Singapore, 169857, Singapore.

Background: Hypertriglyceridemia has emerged as a critical coronary artery disease (CAD) risk factor. Rare loss-of-function (LoF) variants in apolipoprotein C-III have been reported to reduce triglycerides (TG) and are cardioprotective in American Indians and Europeans. However, there is a lack of data in other Europeans and non-Europeans. Also, whether genetically increased plasma TG due to ApoC-III is causally associated with increased CAD risk is still unclear and inconsistent. The objectives of this study were to verify the cardioprotective role of earlier reported six LoF variants of APOC3 in South Asians and other multi-ethnic cohorts and to evaluate the causal association of TG raising common variants for increasing CAD risk.

Methods: We performed gene-centric and Mendelian randomization analyses and evaluated the role of genetic variation encompassing APOC3 for affecting circulating TG and the risk for developing CAD.

Results: One rare LoF variant (rs138326449) with a 37% reduction in TG was associated with lowered risk for CAD in Europeans (p = 0.007), but we could not confirm this association in Asian Indians (p = 0.641). Our data could not validate the cardioprotective role of other five LoF variants analysed. A common variant rs5128 in the APOC3 was strongly associated with elevated TG levels showing a p-value 2.8 × 10. Measures of plasma ApoC-III in a small subset of Sikhs revealed a 37% increase in ApoC-III concentrations among homozygous mutant carriers than the wild-type carriers of rs5128. A genetically instrumented per 1SD increment of plasma TG level of 15 mg/dL would cause a mild increase (3%) in the risk for CAD (p = 0.042).

Conclusions: Our results highlight the challenges of inclusion of rare variant information in clinical risk assessment and the generalizability of implementation of ApoC-III inhibition for treating atherosclerotic disease. More studies would be needed to confirm whether genetically raised TG and ApoC-III concentrations would increase CAD risk.
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http://dx.doi.org/10.1186/s12944-021-01531-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456544PMC
September 2021

Analyses of biomarker traits in diverse UK biobank participants identify associations missed by European-centric analysis strategies.

J Hum Genet 2021 Aug 11. Epub 2021 Aug 11.

Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.

Despite the dramatic underrepresentation of non-European populations in human genetics studies, researchers continue to exclude participants of non-European ancestry, as well as variants rare in European populations, even when these data are available. This practice perpetuates existing research disparities and can lead to important and large effect size associations being missed. Here, we conducted genome-wide association studies (GWAS) of 31 serum and urine biomarker quantitative traits in African (n = 9354), East Asian (n = 2559), and South Asian (n = 9823) ancestry UK Biobank (UKBB) participants. We adjusted for all known GWAS catalog variants for each trait, as well as novel signals identified in a recent European ancestry-focused analysis of UKBB participants. We identify 7 novel signals in African ancestry and 2 novel signals in South Asian ancestry participants (p < 1.61E-10). Many of these signals are highly plausible, including a cis pQTL for the gene encoding gamma-glutamyl transferase and PIEZO1 and G6PD variants with impacts on HbA1c through likely erythrocytic mechanisms. This work illustrates the importance of using the genetic data we already have in diverse populations, with novel discoveries possible in even modest sample sizes.
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http://dx.doi.org/10.1038/s10038-021-00968-0DOI Listing
August 2021

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes.

Nat Commun 2021 06 9;12(1):3505. Epub 2021 Jun 9.

Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.
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http://dx.doi.org/10.1038/s41467-021-23556-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190084PMC
June 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Cohort profile: The Singapore Breast Cancer Cohort (SGBCC), a multi-center breast cancer cohort for evaluation of phenotypic risk factors and genetic markers.

PLoS One 2021 26;16(4):e0250102. Epub 2021 Apr 26.

Saw Swee Hock School of Public Health, National University of Singapore and National University Health Systems, Singapore, Singapore.

This article aims to provide a detailed description of the Singapore Breast Cancer Cohort (SGBCC), an ongoing multi-ethnic cohort established with the overarching goal to identify genetic markers for breast cancer risk, prognosis and treatment response, as well as to understand the ethnic differences in disease risk and outcome in an Asian setting. The cohort comprises of breast cancer patients aged 21 years and above from six public hospitals which diagnose and treat nearly 76% breast cancer cases in Singapore. Self-reported data on sociodemographic and lifestyle, reproductive risk factors, medical history and family history of breast or ovarian cancer is collected using a structured questionnaire. Clinical data on tumour characteristics, and treatment modalities are obtained through medical record. Bio-specimens (blood or saliva) is collected at recruitment. Follow-up on survival information is done through routine linkage with the Registry of Births and Deaths. As of 31 December 2016, 7,768 subjects have been recruited to the study with 76% subjects contributed bio-specimens. The SGBCC provides a valuable platform which offers a unique, large and rich resource for new research ideas on breast cancer related phenotypic risk factors and genetic markers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250102PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075208PMC
October 2021

Association of Genetic Variants for Plasma LRG1 With Rapid Decline in Kidney Function in Patients With Type 2 Diabetes.

J Clin Endocrinol Metab 2021 07;106(8):2384-2394

Clinical Research Unit, Khoo Teck Puat Hospital, Singapore, Singapore.

Context: Elevated levels of plasma leucine-rich α-2-glycoprotein 1 (LRG1), a component of transforming growth factor beta signaling, are associated with development and progression of chronic kidney disease in patients with type 2 diabetes (T2D). However, whether this relationship is causal is uncertain.

Objectives: To identify genetic variants associated with plasma LRG1 levels and determine whether genetically predicted plasma LRG1 contributes to a rapid decline in kidney function (RDKF) in patients with T2D.

Design And Participants: We performed a genome-wide association study of plasma LRG1 among 3694 T2D individuals [1881 (983 Chinese, 420 Malay, and 478 Indian) discovery from Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in Type 2 Diabetes cohort and 1813 (Chinese) validation from Diabetic Nephropathy cohort]. One- sample Mendelian randomization analysis was performed among 1337 T2D Chinese participants with preserved glomerular filtration function [baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2)]. RDKF was defined as an eGFR decline of 3 mL/min/1.73 m2/year or greater.

Results: We identified rs4806985 variant near LRG1 locus robustly associated with plasma LRG1 levels (meta P = 6.66 × 10-16). Among 1337 participants, 344 (26%) developed RDKF, and the rs4806985 variant was associated with higher odds of RDKF (meta odds ratio = 1.23, P = 0.030 adjusted for age and sex). Mendelian randomization analysis provided evidence for a potential causal effect of plasma LRG1 on kidney function decline in T2D (P < 0.05).

Conclusion: We demonstrate that genetically influenced plasma LRG1 increases the risk of RDKF in T2D patients, suggesting plasma LRG1 as a potential treatment target. However, further studies are warranted to elucidate underlying pathways to provide insight into diabetic kidney disease prevention.
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http://dx.doi.org/10.1210/clinem/dgab268DOI Listing
July 2021

Progress in Defining the Genetic Contribution to Type 2 Diabetes in Individuals of East Asian Ancestry.

Curr Diab Rep 2021 04 13;21(6):17. Epub 2021 Apr 13.

Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, 12 Science Drive 2, #10-01, Tahir Foundation Building, Singapore, 117549, Singapore.

Purpose Of Review: Prevalence of type 2 diabetes (T2D) and progression of complications differ between worldwide populations. While obesity is a major contributing risk factor, variations in physiological manifestations, e.g., developing T2D at lower body mass index in some populations, suggest other contributing factors. Early T2D genetic associations were mostly discovered in European ancestry populations. This review describes the progression of genetic discoveries associated with T2D in individuals of East Asian ancestry in the last 10 years and highlights the shared genetic susceptibility between the population groups and additional insights into genetic contributions to T2D.

Recent Findings: Through increased sample size and power, new genetic associations with T2D were discovered in East Asian ancestry populations, often with higher allele frequencies than European ancestry populations. As we continue to generate maps of T2D-associated variants across diverse populations, there will be a critical need to expand and diversify other omics resources to enable integration for clinical translation.
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http://dx.doi.org/10.1007/s11892-021-01388-2DOI Listing
April 2021

Common variants in SOX-2 and congenital cataract genes contribute to age-related nuclear cataract.

Commun Biol 2020 12 11;3(1):755. Epub 2020 Dec 11.

Institute of Molecular and Cell Biology, 138673, Singapore, Singapore.

Nuclear cataract is the most common type of age-related cataract and a leading cause of blindness worldwide. Age-related nuclear cataract is heritable (h = 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) with nuclear cataract and identified five new loci associated with this disease: SOX2-OT (rs9842371, P = 1.7 × 10), TMPRSS5 (rs4936279, P = 2.5 × 10), LINC01412 (rs16823886, P = 1.3 × 10), GLTSCR1 (rs1005911, P = 9.8 × 10), and COMMD1 (rs62149908, P = 1.2 × 10). 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.
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http://dx.doi.org/10.1038/s42003-020-01421-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733496PMC
December 2020

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.

Nat Genet 2020 12 23;52(12):1314-1332. Epub 2020 Nov 23.

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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http://dx.doi.org/10.1038/s41588-020-00713-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610439PMC
December 2020

Coffee, Black Tea, and Green Tea Consumption in Relation to Plasma Metabolites in an Asian Population.

Mol Nutr Food Res 2020 Oct 29:e2000527. Epub 2020 Oct 29.

Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, 117549, Singapore.

Scope: Coffee and tea are among the most popular beverages in the world. However, the association between habitual coffee, green tea, and black tea consumption with metabolomics profiles in Asian populations remain largely unknown.

Methods And Results: 158 metabolites (14 amino acids, 45 acylcarnitines, and 99 sphingolipids) in the blood plasma of participants are measured from the population-based Singapore Prospective Study Program cohort using mass spectrometry (MS). Linear regression models are used to obtain the estimates for the association between coffee and tea consumption with metabolite levels, adjusted for potential confounders and false discovery rate (FDR). Coffee consumption is significantly associated with higher levels of 63 sphingolipids (29 sphingomyelins, 32 ceramides, a sphingosine-1-phosphate, and a sphingosine) and lower levels of 13 acylcarnitines and alanine. Black tea consumption is significantly associated with higher levels of eight sphingolipids, and lower levels of an amino acid, whereas green tea is significantly inversely associated with four metabolites (C8:1-OH acylcarnitine, ganglioside GM3 d18:1/16:0, sphingomyelins d18:2/18:0 and d18:1/14:0).

Conclusions: Coffee, black tea, and green tea consumption are associated with plasma levels of certain classes of sphingolipids and acylcarnitines in an Asian population, particularly sphingomyelins, which may mediate the health benefits of these beverages.
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http://dx.doi.org/10.1002/mnfr.202000527DOI Listing
October 2020

Serum acylcarnitines and amino acids and risk of type 2 diabetes in a multiethnic Asian population.

BMJ Open Diabetes Res Care 2020 10;8(1)

Saw Swee Hock School of Public Health, National University of Singapore, Singapore.

Introduction: We evaluated whether concentrations of serum acylcarnitines and amino acids are associated with risk of type 2 diabetes and can improve predictive diabetes models in an Asian population.

Research Design And Methods: We used data from 3313 male and female participants from the Singapore Prospective Study Program cohort who were diabetes-free at baseline. The average age at baseline was 48.0 years (SD: 11.9 years), and participants were of Chinese, Malay, and Indian ethnicity. Diabetes cases were identified through self-reported physician diagnosis, fasting glucose and glycated hemoglobin concentrations, and linkage to national disease registries. We measured fasting serum concentrations of 45 acylcarnitines and 14 amino acids. The association between metabolites and incident diabetes was modeled using Cox proportional hazards regression with adjustment for age, sex, ethnicity, height, and parental history of diabetes, and correction for multiple testing. Metabolites were added to the Atherosclerosis Risk in Communities (ARIC) predictive diabetes risk model to assess whether they could increase the area under the receiver operating characteristic curve (AUC).

Results: Participants were followed up for an average of 8.4 years (SD: 2.1 years), during which time 314 developed diabetes. Branched-chain amino acids (HR: 1.477 per SD; 95% CI 1.325 to 1.647) and the alanine to glycine ratio (HR: 1.572; 95% CI 1.426 to 1.733) were most strongly associated with diabetes risk. Additionally, the acylcarnitines C4 and C16-OH, and the amino acids alanine, combined glutamate/glutamine, ornithine, phenylalanine, proline, and tyrosine were significantly associated with higher diabetes risk, and the acylcarnitine C8-DC and amino acids glycine and serine with lower risk. Adding selected metabolites to the ARIC model resulted in a significant increase in AUC from 0.836 to 0.846.

Conclusions: We identified acylcarnitines and amino acids associated with risk of type 2 diabetes in an Asian population. A subset of these modestly improved the prediction of diabetes when added to an established diabetes risk model.
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http://dx.doi.org/10.1136/bmjdrc-2020-001315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534670PMC
October 2020

Genome-Wide Association for HbA1c in Malay Identified Deletion on SLC4A1 that Influences HbA1c Independent of Glycemia.

J Clin Endocrinol Metab 2020 12;105(12)

Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.

Context: Glycated hemoglobin A1c (HbA1c) level is used to screen and diagnose diabetes. Genetic determinants of HbA1c can vary across populations and many of the genetic variants influencing HbA1c level were specific to populations.

Objective: To discover genetic variants associated with HbA1c level in nondiabetic Malay individuals.

Design And Participants: We conducted a genome-wide association study (GWAS) analysis for HbA1c using 2 Malay studies, the Singapore Malay Eye Study (SiMES, N = 1721 on GWAS array) and the Living Biobank study (N = 983 on GWAS array and whole-exome sequenced). We built a Malay-specific reference panel to impute ethnic-specific variants and validate the associations with HbA1c at ethnic-specific variants.

Results: Meta-analysis of the 1000 Genomes imputed array data identified 4 loci at genome-wide significance (P < 5 × 10-8). Of the 4 loci, 3 (ADAM15, LINC02226, JUP) were novel for HbA1c associations. At the previously reported HbA1c locus ATXN7L3-G6PC3, association analysis using the exome data fine-mapped the HbA1c associations to a 27-bp deletion (rs769664228) at SLC4A1 that reduced HbA1c by 0.38 ± 0.06% (P = 3.5 × 10-10). Further imputation of this variant in SiMES confirmed the association with HbA1c at SLC4A1. We also showed that these genetic variants influence HbA1c level independent of glucose level.

Conclusion: We identified a deletion at SLC4A1 associated with HbA1c in Malay. The nonglycemic lowering of HbA1c at rs769664228 might cause individuals carrying this variant to be underdiagnosed for diabetes or prediabetes when HbA1c is used as the only diagnostic test for diabetes.
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http://dx.doi.org/10.1210/clinem/dgaa658DOI Listing
December 2020

Diet, Physical Activity and Adiposity as Determinants of Circulating Amino Acid Levels in a Multiethnic Asian Population.

Nutrients 2020 Aug 27;12(9). Epub 2020 Aug 27.

Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117549, Singapore.

Profiles of circulating amino acids have been associated with cardiometabolic diseases. We investigated the associations between dietary protein intake, physical activity and adiposity and serum amino acid profiles in an Asian population. We used data from 3009 male and female participants from the Singapore Prospective Study Program cohort. Dietary and physical activity data were obtained from validated questionnaires; anthropometric measurements were collected during a health examination; and fasting concentrations of 16 amino acids were measured using targeted LC-MS. The association between lifestyle factors and amino acid levels was modeled using multiple linear regression with adjustment for other sociodemographic and lifestyle factors and correction for multiple testing. We observed significant associations between seafood intake (-coefficient 0.132, 95% CI 0.006, 0.257 for a 100% increment), physical activity (-coefficient -0.096, 95% CI -0.183, -0.008 in the highest versus lowest quartile) and adiposity (BMI -coefficient 0.062, 95% CI 0.054, 0.070 per kg/m; waist circumference -coefficient 0.034, 95% CI 0.031, 0.037 per cm) and branched-chain amino acid levels (expressed per-SD). We also observed significant interactions with sex for the association between meat and seafood and total intakes and BCAA levels ( for interaction 0.007), which were stronger in females than in males. Our findings suggest novel associations between modifiable lifestyle factors and amino acid levels in Asian populations.
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http://dx.doi.org/10.3390/nu12092603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551953PMC
August 2020

European polygenic risk score for prediction of breast cancer shows similar performance in Asian women.

Nat Commun 2020 07 31;11(1):3833. Epub 2020 Jul 31.

Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore, Singapore.

Polygenic risk scores (PRS) have been shown to predict breast cancer risk in European women, but their utility in Asian women is unclear. Here we evaluate the best performing PRSs for European-ancestry women using data from 17,262 breast cancer cases and 17,695 controls of Asian ancestry from 13 case-control studies, and 10,255 Chinese women from a prospective cohort (413 incident breast cancers). Compared to women in the middle quintile of the risk distribution, women in the highest 1% of PRS distribution have a ~2.7-fold risk and women in the lowest 1% of PRS distribution has ~0.4-fold risk of developing breast cancer. There is no evidence of heterogeneity in PRS performance in Chinese, Malay and Indian women. A PRS developed for European-ancestry women is also predictive of breast cancer risk in Asian women and can help in developing risk-stratified screening programmes in Asia.
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http://dx.doi.org/10.1038/s41467-020-17680-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395776PMC
July 2020

Using off-target data from whole-exome sequencing to improve genotyping accuracy, association analysis and polygenic risk prediction.

Brief Bioinform 2021 05;22(3)

Ministry of Education Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Whole-exome sequencing (WES) has been widely used to study the role of protein-coding variants in genetic diseases. Non-coding regions, typically covered by sparse off-target data, are often discarded by conventional WES analyses. Here, we develop a genotype calling pipeline named WEScall to analyse both target and off-target data. We leverage linkage disequilibrium shared within study samples and from an external reference panel to improve genotyping accuracy. In an application to WES of 2527 Chinese and Malays, WEScall can reduce the genotype discordance rate from 0.26% (SE= 6.4 × 10-6) to 0.08% (SE = 3.6 × 10-6) across 1.1 million single nucleotide polymorphisms (SNPs) in the deeply sequenced target regions. Furthermore, we obtain genotypes at 0.70% (SE = 3.0 × 10-6) discordance rate across 5.2 million off-target SNPs, which had ~1.2× mean sequencing depth. Using this dataset, we perform genome-wide association studies of 10 metabolic traits. Despite of our small sample size, we identify 10 loci at genome-wide significance (P < 5 × 10-8), including eight well-established loci. The two novel loci, both associated with glycated haemoglobin levels, are GPATCH8-SLC4A1 (rs369762319, P = 2.56 × 10-12) and ROR2 (rs1201042, P = 3.24 × 10-8). Finally, using summary statistics from UK Biobank and Biobank Japan, we show that polygenic risk prediction can be significantly improved for six out of nine traits by incorporating off-target data (P < 0.01). These results demonstrate WEScall as a useful tool to facilitate WES studies with decent amounts of off-target data.
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http://dx.doi.org/10.1093/bib/bbaa084DOI Listing
May 2021

Exploring Factors Underlying Ethnic Difference in Age-related Macular Degeneration Prevalence.

Ophthalmic Epidemiol 2020 10 8;27(5):399-408. Epub 2020 Jun 8.

Centre for Vision Research, Department of Ophthalmology, Westmead Institute for Medical Research, University of Sydney , Westmead, NSW, Australia.

Aims: To assess contributions of dietary and genetic factors to ethnic differences in AMD prevalence.

Design: Population-based analytical study.

Methods: In the Blue Mountains Eye Study, Australia (European ancestry n = 2826) and Multi-Ethnic Cohort Study, Singapore (Asian ancestry, n = 1900), AMD was assessed from retinal photographs. Patterns of dietary composition and scores of the Alternative Healthy Eating Index were computed using food frequency questionnaire data. Genetic susceptibility to AMD was determined using either single nucleotide polymorphisms (SNPs) of the c and genes, or combined odds-weighted genetic risk scores of 24 AMD-associated SNPs. Associations of AMD with ethnicity, diet, and genetics were assessed using logistic regression. Six potential mediators covering genetic, diet and lifestyle factors were assessed for their contributions to AMD risk difference between the two samples using mediation analyses.

Results: Age-standardized prevalence of any (early or late) AMD was higher in the European (16%) compared to Asian samples (9%, < .01). Mean AMD-related genetic risk scores were also higher in European (33.3 ± 4.4) than Asian (Chinese) samples (31.7 ± 3.7, < .001). In a model simultaneously adjusting for age, ethnicity, genetic susceptibility and Alternative Healthy Eating Index scores, only age and genetic susceptibility were significantly associated with AMD. Genetic risk scores contributed 19% of AMD risk difference between the two samples while intake of polyunsaturated fatty acids contributed 7.2%.

Conclusion: Genetic susceptibility to AMD was higher in European compared to Chinese samples and explained more of the AMD risk difference between the two samples than the dietary factors investigated.
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http://dx.doi.org/10.1080/09286586.2020.1762229DOI Listing
October 2020

Identification of type 2 diabetes loci in 433,540 East Asian individuals.

Nature 2020 06 6;582(7811):240-245. Epub 2020 May 6.

Vanderbilt Genetics Institute, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Meta-analyses of genome-wide association studies (GWAS) have identified more than 240 loci that are associated with type 2 diabetes (T2D); however, most of these loci have been identified in analyses of individuals with European ancestry. Here, to examine T2D risk in East Asian individuals, we carried out a meta-analysis of GWAS data from 77,418 individuals with T2D and 356,122 healthy control individuals. In the main analysis, we identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 61 loci that are newly implicated in predisposition to T2D. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. Previously undescribed associations include signals in or near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect the differentiation of muscle and adipose cells. At another locus, expression quantitative trait loci at two overlapping T2D signals affect two genes-NKX6-3 and ANK1-in different tissues. Association studies in diverse populations identify additional loci and elucidate disease-associated genes, biology, and pathways.
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http://dx.doi.org/10.1038/s41586-020-2263-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292783PMC
June 2020

Cohort profile: the Singapore diabetic cohort study.

BMJ Open 2020 05 30;10(5):e036443. Epub 2020 May 30.

Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore

Purpose: The diabetic cohort (DC) was set up to study the determinants of complications in individuals with type 2 diabetes and examine the role of genetic, physiological and lifestyle factors in the development of complications in these individuals.

Participants: A total of 14 033 adult participants with type 2 diabetes were recruited from multiple public sector polyclinics and hospital outpatient clinics in Singapore between November 2004 and November 2010. The first round of follow-up was conducted for 4131 participants between 2012 and 2016; the second round of follow-up started in 2016 and is expected to end in 2021. A questionnaire survey, physical assessments, blood and urine sample collection were conducted at recruitment and each follow-up visit. The data set also includes genetic data and linkage to medical and administrative records for recruited participants.

Findings To Date: Data from the cohort have been used to identify determinants of diabetes and related complications. The longitudinal data of medical records have been used to analyse diabetes control over time and its related outcomes. The cohort has also contributed to the identification of genetic loci associated with type 2 diabetes and diabetic kidney disease in collaboration with other large cohort studies. About 25 scientific papers based on the DC data have been published up to May 2019.

Future Plans: The rich data in DC can be used for various types of research to study disease-related complications in patients with type 2 diabetes. We plan to further investigate disease progression and new biomarkers for common diabetic complications, including diabetic kidney disease and diabetic neuropathy.
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http://dx.doi.org/10.1136/bmjopen-2019-036443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264641PMC
May 2020

Mendelian randomization analysis does not support causal associations of birth weight with hypertension risk and blood pressure in adulthood.

Eur J Epidemiol 2020 Jul 7;35(7):685-697. Epub 2020 May 7.

Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, Lund University, 21741, Malmö, Sweden.

Epidemiology studies suggested that low birthweight was associated with a higher risk of hypertension in later life. However, little is known about the causality of such associations. In our study, we evaluated the causal association of low birthweight with adulthood hypertension following a standard analytic protocol using the study-level data of 183,433 participants from 60 studies (CHARGE-BIG consortium), as well as that with blood pressure using publicly available summary-level genome-wide association data from EGG consortium of 153,781 participants, ICBP consortium and UK Biobank cohort together of 757,601 participants. We used seven SNPs as the instrumental variable in the study-level analysis and 47 SNPs in the summary-level analysis. In the study-level analyses, decreased birthweight was associated with a higher risk of hypertension in adults (the odds ratio per 1 standard deviation (SD) lower birthweight, 1.22; 95% CI 1.16 to 1.28), while no association was found between genetically instrumented birthweight and hypertension risk (instrumental odds ratio for causal effect per 1 SD lower birthweight, 0.97; 95% CI 0.68 to 1.41). Such results were consistent with that from the summary-level analyses, where the genetically determined low birthweight was not associated with blood pressure measurements either. One SD lower genetically determined birthweight was not associated with systolic blood pressure (β = - 0.76, 95% CI - 2.45 to 1.08 mmHg), 0.06 mmHg lower diastolic blood pressure (β = - 0.06, 95% CI - 0.93 to 0.87 mmHg), or pulse pressure (β = - 0.65, 95% CI - 1.38 to 0.69 mmHg, all p > 0.05). Our findings suggest that the inverse association of birthweight with hypertension risk from observational studies was not supported by large Mendelian randomization analyses.
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http://dx.doi.org/10.1007/s10654-020-00638-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867117PMC
July 2020

Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.

Mol Psychiatry 2021 06 5;26(6):2111-2125. Epub 2020 May 5.

Health Disparities Research Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
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http://dx.doi.org/10.1038/s41380-020-0719-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641978PMC
June 2021

Association of variants with hemoglobin A1c and impact on diabetes diagnosis in East Asian individuals.

BMJ Open Diabetes Res Care 2020 03;8(1)

Saw Swee Hock School of Public Health, National University of Singapore, Singapore

Objective: Hemoglobin A1c (HbA1c) accuracy is important for diabetes diagnosis and estimation of overall glycemia. The Asahi variant which causes glucose-6-phosphate dehydrogenase (G6PD) deficiency has been shown to lower HbA1c independently of glycemia in African ancestry populations. As different variants occur in Asian ancestry, we sought to identify Asian-specific variants associated with HbA1c.

Research Design And Methods: In eight Asian population-based cohorts, we performed imputation on the X chromosome using the 1000 Genomes reference panel and tested for association with HbA1c (10 005 East Asians and 2051 South Asians). Results were meta-analyzed across studies. We compared the proportion of individuals classified as having diabetes/pre-diabetes by fasting glucose ≥100 mg/dL or HbA1c ≥5.7% units among carriers and non-carriers of HbA1c-associated variants.

Results: The strongest association was a missense variant (-Canton, rs72554665, minor allele frequency=2.2%, effect in men=-0.76% unit, 95% CI -0.88 to -0.64, p=1.25×10, n=2844). Conditional analyses identified a secondary distinct signal, missense variant (-Kaiping, rs72554664, minor allele frequency=1.6%, effect in men=-1.12 % unit, 95% CI -1.32 to -0.92, p=3.12×10, p=7.57×10). Adjusting for glucose did not attenuate their effects. The proportion of individuals with fasting glucose ≥100 mg/dL did not differ by carrier status of -Canton (p=0.21). Whereas the proportion of individuals with HbA1c ≥5.7% units was lower in carriers (5%) compared with non-carriers of -Canton (30%, p=0.03).

Conclusions: We identified two variants in East Asian men associated with non-glycemic lowering of HbA1c. Carriers of these variants are more likely to be underdiagnosed for diabetes or pre-diabetes than non-carriers if screened by HbA1c without confirmation by direct glucose measurements.
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http://dx.doi.org/10.1136/bmjdrc-2019-001091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103857PMC
March 2020

Genome-wide meta-analysis associates GPSM1 with type 2 diabetes, a plausible gene involved in skeletal muscle function.

J Hum Genet 2020 Apr 21;65(4):411-420. Epub 2020 Jan 21.

National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China, 210016.

Genome-wide association studies (GWASs) have identified many genetic variations associated with type 2 diabetes mellitus (T2DM) in Asians, but understanding the functional genetic variants that influence traits is often a complex process. In this study, fine mapping and other analytical strategies were performed to investigate the effects of G protein signaling modulator 1 (GPSM1) on insulin resistance in skeletal muscle. A total of 128 single-nucleotide polymorphisms (SNPs) within GPSM1 were analysed in 21,897 T2DM cases and 32,710 healthy controls from seven GWASs. The SNP rs28539249 in intron 9 of GPSM1 showed a nominally significant association with T2DM in Asians (OR = 1.07, 95% CI = 1.04-1.10, P < 10). The GPSM1 mRNA was increased in skeletal muscle and correlated with T2DM traits across obese mice model. An eQTL for the cis-acting regulation of GPSM1 expression in human skeletal muscle was identified for rs28539249, and the increased GPSM1 expression related with T2DM traits within GEO datasets. Another independent Asian cohort showed that rs28539249 is associated with the skeletal muscle expression of CACFD1, GTF3C5, SARDH, and FAM163B genes, which are functionally enriched for endoplasmic reticulum stress (ERS) and unfolded protein response (UPR) pathways. Moreover, rs28539249 locus was predicted to disrupt regulatory regions in human skeletal muscle with enriched epigenetic marks and binding affinity for CTCF. Supershift EMSA assays followed luciferase assays demonstrated the CTCF specifically binding to rs28539249-C allele leading to decreased transcriptional activity. Thus, the post-GWAS annotation confirmed the Asian-specific association of genetic variant in GPSM1 with T2DM, suggesting a role for the variant in the regulation in skeletal muscle.
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http://dx.doi.org/10.1038/s10038-019-0720-3DOI Listing
April 2020

Multiple Biomarkers Improved Prediction for the Risk of Type 2 Diabetes Mellitus in Singapore Chinese Men and Women.

Diabetes Metab J 2020 04 22;44(2):295-306. Epub 2019 Nov 22.

Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background: Multiple biomarkers have performed well in predicting type 2 diabetes mellitus (T2DM) risk in Western populations. However, evidence is scarce among Asian populations.

Methods: Plasma triglyceride-to-high density lipoprotein (TG-to-HDL) ratio, alanine transaminase (ALT), high-sensitivity C-reactive protein (hs-CRP), ferritin, adiponectin, fetuin-A, and retinol-binding protein 4 were measured in 485 T2DM cases and 485 age-and-sex matched controls nested within the prospective Singapore Chinese Health Study cohort. Participants were free of T2DM at blood collection (1999 to 2004), and T2DM cases were identified at the subsequent follow-up interviews (2006 to 2010). A weighted biomarker score was created based on the strengths of associations between these biomarkers and T2DM risks. The predictive utility of the biomarker score was assessed by the area under receiver operating characteristics curve (AUC).

Results: The biomarker score that comprised of four biomarkers (TG-to-HDL ratio, ALT, ferritin, and adiponectin) was positively associated with T2DM risk ( trend <0.001). Compared to the lowest quartile of the score, the odds ratio was 12.0 (95% confidence interval [CI], 5.43 to 26.6) for those in the highest quartile. Adding the biomarker score to a base model that included smoking, history of hypertension, body mass index, and levels of random glucose and insulin improved AUC significantly from 0.81 (95% CI, 0.78 to 0.83) to 0.83 (95% CI, 0.81 to 0.86; =0.002). When substituting the random glucose levels with glycosylated hemoglobin in the base model, adding the biomarker score improved AUC from 0.85 (95% CI, 0.83 to 0.88) to 0.86 (95% CI, 0.84 to 0.89; =0.032).

Conclusion: A composite score of blood biomarkers improved T2DM risk prediction among Chinese.
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http://dx.doi.org/10.4093/dmj.2019.0020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188981PMC
April 2020

Associations of autozygosity with a broad range of human phenotypes.

Nat Commun 2019 10 31;10(1):4957. Epub 2019 Oct 31.

Department of Neurology, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht University, Utrecht, 3584 CX, The Netherlands.

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.
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http://dx.doi.org/10.1038/s41467-019-12283-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823371PMC
October 2019

Associations with metabolites in Chinese suggest new metabolic roles in Alzheimer's and Parkinson's diseases.

Hum Mol Genet 2020 01;29(2):189-201

Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.

Metabolites are small intermediate products of cellular metabolism perturbed in a variety of complex disorders. Identifying genetic markers associated with metabolite concentrations could delineate disease-related metabolic pathways in humans. We tested genetic variants for associations with 136 metabolites in 1954 Chinese from Singapore. At a conservative genome-wide threshold (3.7 × 10-10), we detected 1899 variant-metabolite associations at 16 genetic loci. Three loci (ABCA7, A4GALT, GSTM2) represented novel associations with metabolites, with the strongest association observed between ABCA7 and d18:1/24:1 dihexosylceramide. Among 13 replicated loci, we identified six new variants independent of previously reported metabolite or lipid signals. We observed variant-metabolite associations at two loci (ABCA7, CHCHD2) that have been linked to neurodegenerative diseases. At SGPP1 and SPTLC3 loci, genetic variants showed preferential selectivity for sphingolipids with d16 (rather than d18) sphingosine backbone, including sphingosine-1-phosphate (S1P). Our results provide new genetic associations for metabolites and highlight the role of metabolites as intermediate modulators in disease metabolic pathways.
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http://dx.doi.org/10.1093/hmg/ddz246DOI Listing
January 2020
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