132 results found
Zhang W, Reeves JJ, Kooner JS, 2022, Accelerated ageing is associated with increased Covid-19 severity and differences across ethnic groups may exist, Frontiers in Public Health, ISSN: 2296-2565
Background:While increased age is an established risk factor for COVID-19, there is great heterogeneity in outcomes within age groups. This isbecause chronological age does not reflect health, unlike biological age. We intend to investigate the association betweenaccelerated ageing and COVID-19 outcomes through the lens of three measures, namely phenotypic age acceleration(PhenoAgeAccel), telomere length (Adjusted T/S Ratio) and facial ageing, and to examine whether there are differences acrossethnic groups.Methods:Taking participants from the UK Biobank, we associated accelerated ageing with severe COVID-19 outcomes, defined as COVID-related hospitalisation or death. Separate logistic regressions models were created for age and the three accelerated ageing-related variables, adjusting for a variety of covariates in each model. Multivariable logistic regression models were also createdwithin White, Black, Asian and Other ethnic groups to assess for potential differing associations. Forward likelihood ratio logisticregression models were created to evaluate importance of the variables and to assess for patterns of association across the totalpopulation and ethnic groups.Results:After adjusting for all covariates, the odds ratio (OR) and 95% confidence interval (95% CI) of COVID-19 severe outcomes for age was1.080 (1.074-1.086). After further adjusting age for the accelerated ageing variables, the ORs were 1.029 (1.020-1.039) forPhenoAgeAccel and 0.847 (0.772-0.929) for Facial Ageing’s ‘Younger Than You Are’ while Adjusted T/S ratio and ‘Older Than You Are’were statistically insignificant. The OR for age remained similar across ethnic groups. Both PhenoAgeAccel and younger facial agesin the White population and PhenoAgeAccel in the Black population had ORs of 1.031 (1.021-1.042), 0.853 (0.774-0.939), and 1.049(1.001-1.100), respectively. Both Adjusted T/S Ratio and older facial ages showed statistical insignificance in all ethnicities. In
Yengo L, Vedantam S, Marouli E, et al., 2022, A saturated map of common genetic variants associated with human height, NATURE, Vol: 610, Pages: 704-+, ISSN: 0028-0836
Ramdas S, Judd J, Graham SE, et al., 2022, A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 109, Pages: 1366-1387, ISSN: 0002-9297
Winkler TW, Rasheed H, Teumer A, et al., 2022, Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals, Communications Biology, Vol: 5, ISSN: 2399-3642
Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.
Mahajan A, Spracklen CN, Zhang W, et al., 2022, Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation, NATURE GENETICS, Vol: 54, Pages: 560-+, ISSN: 1061-4036
Loh M, Zhang W, Ng HK, et al., 2022, Identification of genetic effects underlying type 2 diabetes in South Asian and European populations (vol 5, 329, 2022), COMMUNICATIONS BIOLOGY, Vol: 5
Loh M, Zhang W, Ng HK, et al., 2022, Identification of genetic effects underlying Type 2 Diabetes in South Asian and European populations, Communications Biology, Vol: 5, ISSN: 2399-3642
South Asians are at high risk of developing type 2 diabetes (T2D). We carried out a genome-wide association meta-analysis with South Asian T2D cases (n=16,677) and controls (n=33,856), followed by combined analyses with Europeans (neff=231,420). We identify 21 novel genetic loci for significant association with T2D (P=4.7x10-8 to 5.2x10-12), to the best of our knowledge at the point of analysis. The loci are enriched for regulatory features, including DNA methylation and gene expression in relevant tissues, and highlight CHMP4B, PDHB, LRIG1 and other genes linked to adiposity and glucose metabolism. A polygenic risk score based on South Asian-derived summary statistics shows ~4-fold higher risk for T2D between the top and bottom quartile. Our results provide further insights into the genetic mechanisms underlying T2D, and highlight the opportunities for discovery from joint analysis of data from across ancestral populations.
Hawe JS, Wilson R, Schmid KT, et al., 2022, Genetic variation influencing DNA methylation provides insights into molecular mechanisms regulating genomic function, NATURE GENETICS, Vol: 54, Pages: 18-+, ISSN: 1061-4036
Graham SE, Clarke SL, Wu K-HH, et al., 2021, The power of genetic diversity in genome-wide association studies of lipids, NATURE, Vol: 600, Pages: 675-+, ISSN: 0028-0836
Goyal S, Tanigawa Y, Zhang W, et al., 2021, APOC3 genetic variation, serum triglycerides, and risk of coronary artery disease in Asian Indians, Europeans, and other ethnic groups, LIPIDS IN HEALTH AND DISEASE, Vol: 20
Chen J, Spracklen CN, Marenne G, et al., 2021, The trans-ancestral genomic architecture of glycemic traits, Nature Genetics, Vol: 53, Pages: 840-860, ISSN: 1061-4036
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 × 10−8), 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.
Surendran P, Feofanova EV, Lahrouchi N, et al., 2021, Publisher Correction: Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals, Nature Genetics, Vol: 53, Pages: 1-2, ISSN: 1061-4036
Gomez-Alonso MDC, Kretschmer A, Wilson R, et al., 2021, DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures, CLINICAL EPIGENETICS, Vol: 13, ISSN: 1868-7075
Surendran P, Gao H, Zhang W, et al., 2020, Discovery of rare variants associated with blood pressure regulation trhough meta-analaysis of 1.3 million individuals, Nature Genetics, Vol: 52, Pages: 1314-1332, ISSN: 1061-4036
Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency, MAF > 0.05). In a meta-analysis of up to >1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (MAF≤ 0.01) variant BP associations (P < 5 × 10-8), of which 32 were in new BP-associated loci and 55 were independent BP-associated SNVs 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 (e.g.GATA5, 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.
Spracklen CN, Horikoshi M, Kim YJ, et al., 2020, Identification of type 2 diabetes loci in 433,540 East Asian individuals, NATURE, Vol: 582, Pages: 240-+, ISSN: 0028-0836
Ochoa-Rosales C, Portilla-Fernandez E, Nano J, et al., 2020, Epigenetic Link Between Statin Therapy and Type 2 Diabetes, DIABETES CARE, Vol: 43, Pages: 875-884, ISSN: 0149-5992
Clark DW, Zhang W, Gao H, et al., 2019, Associations of autozygosity with a broad range of human phenotypes, Nature Communications, Vol: 10, ISSN: 2041-1723
In many species, the offspring of related parents suffer reduced vigor, survival and reproductive success, a phenomenon known as inbreeding depression1. In humans, the importance of this effect has remained unclear2, partly because reproduction between close relatives is both rare in many cultures and frequently associated with confounding social factors3. Here, using genomic inbreeding coefficients4 (FROH) for >1.3 million individuals, we show that FROH is significantly associated (P < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. Increased FROH is associated with reduced reproductive success (decreased number and likelihood of having children, older age at first sex and first birth, decreased number of sexual partners), as well as reduced risk-taking behaviour (alcohol intake, ever-smoked, self-reported risk taking) and increased disease risk (self-reported overall health, and risk factors including grip strength and heart rate). The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. These effects are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants causing inbreeding depression are predominantly rare. For a subset of traits, the effect of FROH differs significantly between men and women. Indeed, an increased FROH is associated with decreased total and LDL cholesterol in men, raising the possibility that increases in these traits may have benefited evolutionary fitness, despite being known coronary risk factors. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of environmental confounding. We conclude that inbreeding depression influences a broad range of human phenotypes through the action of rare, recessive variants.
Tin A, Marten J, Kuhns VLH, et al., 2019, Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels, NATURE GENETICS, Vol: 51, Pages: 1459-+, ISSN: 1061-4036
Erzurumluoglu AM, Chambers JC, Elliott P, et al., 2019, Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci, Molecular Psychiatry, Vol: 25, Pages: 2392-2409, ISSN: 1359-4184
Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10−8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10−8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10−3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.
Sung YJ, de Las Fuentes L, Winkler TW, et al., 2019, A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure, Human Molecular Genetics, Vol: 28, Pages: 2615-2633, ISSN: 0964-6906
Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene–smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene–smoking interaction analysis and 38 were newly identified (P < 5 × 10−8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.
Turcot V, Lu Y, Highland HM, et al., 2019, Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity, Nature Genetics, Vol: 51, Pages: 1191-1192, ISSN: 1061-4036
In the HTML version of this article initially published, the author groups ‘CHD Exome+ Consortium’, ‘EPIC-CVD Consortium’, ‘ExomeBP Consortium’, ‘Global Lipids Genetic Consortium’, ‘GoT2D Genes Consortium’, ‘EPIC InterAct Consortium’, ‘INTERVAL Study’, ‘ReproGen Consortium’, ‘T2D-Genes Consortium’, ‘The MAGIC Investigators’ and ‘Understanding Society Scientific Group’ appeared at the end of the author list but should have appeared earlier in the list, after author Krina T. Zondervan. The errors have been corrected in the HTML version of the article.
Brazel DM, Jiang Y, Hughey JM, et al., 2019, Exome chip meta-analysis fine maps causal variants and elucidates the genetic architecture of rare coding variants in smoking and alcohol use, Biological Psychiatry, Vol: 85, Pages: 946-955, ISSN: 0006-3223
Background: Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk. Methods: We analyzed ∼250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci. Results: Meta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1% to 2.2% of phenotypic variance, reflecting 11% to 18% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95% credible intervals. Conclusions: Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior.
de Vries PS, Brown MR, Bentley AR, et al., 2019, Multi-ancestry genome-wide association study of lipid levels incorporating gene-alcohol interactions, American Journal of Epidemiology, Vol: 188, Pages: 1033-1054, ISSN: 1476-6256
An individual'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 multi-ancestry 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 five ancestry groups. Genetic main and interaction effects were jointly assessed by 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 Stage 1 and Stage 2, 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 (PCSK5, VEGFB, and A1CF) with a putative role in lipid metabolism based on existing evidence from cellular and experimental models.
Wuttke M, Li Y, Li M, et al., 2019, A catalog of genetic loci associated with kidney function from analyses of a million individuals, Nature Genetics, Vol: 51, Pages: 957-972, ISSN: 1061-4036
Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
De Silva NMG, Borges MC, Hingorani A, et al., 2019, Liver function and risk of type 2 diabetes: bidirectional mendelian randomization study., Diabetes, Vol: 68, Pages: 1681-1691, ISSN: 0012-1797
Liver dysfunction and type 2 diabetes (T2D) are consistently associated. However, it is currently unknown whether liver dysfunction contributes to, results from or is merely correlated with T2D due to confounding. We used Mendelian randomization (MR) to investigate the presence and direction of any causal relation between liver function and T2D risk including up to 64,094 T2D cases and 607,012 controls. Several biomarkers were used as proxies of liver function [i.e. alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT)]. Genetic variants strongly associated with each liver function marker were used to investigate the effect of liver function on T2D risk. In addition, genetic variants strongly associated with T2D risk and with fasting insulin were used to investigate the effect of predisposition to T2D and insulin resistance, respectively, on liver function. Genetically predicted higher circulating ALT and AST were related to increased risk of T2D. There was a modest negative association of genetically predicted ALP with T2D risk and no evidence of association between GGT and T2D risk. Genetically predisposition to higher fasting insulin, but not to T2D, was related to increased circulating ALT. Since circulating ALT and AST are markers of NAFLD, these findings provide some support for insulin resistance resulting in NAFLD, which in turn increases T2D risk.
Bentley AR, Sung YJ, Brown MR, et al., 2019, Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids, Nature Genetics, Vol: 51, Pages: 636-648, ISSN: 1061-4036
The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene–smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.
BackgroundLean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass.ObjectivesTo determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci.MethodsWe performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms).ResultsSeven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as “sumo wrestler” loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed “body builder” loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in “body builder” loci were associated with metabolic protection.ConclusionsIn conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.
Evangelou E, Warren HR, Mosen-Ansorena D, et al., 2018, Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits (vol 50, pg 1412, 2018), NATURE GENETICS, Vol: 50, Pages: 1755-1755, ISSN: 1061-4036
Parmar P, Lowry E, Cugliari G, et al., 2018, Association of maternal prenatal smoking GFI1-locus and cardiometabolic phenotypes in 18,212 adults, EBioMedicine, Vol: 38, Pages: 206-216, ISSN: 2352-3964
BackgroundDNA methylation at the GFI1-locus has been repeatedly associated with exposure to smoking from the foetal period onwards. We explored whether DNA methylation may be a mechanism that links exposure to maternal prenatal smoking with offspring's adult cardio-metabolic health.MethodsWe meta-analysed the association between DNA methylation at GFI1-locus with maternal prenatal smoking, adult own smoking, and cardio-metabolic phenotypes in 22 population-based studies from Europe, Australia, and USA (n = 18,212). DNA methylation at the GFI1-locus was measured in whole-blood. Multivariable regression models were fitted to examine its association with exposure to prenatal and own adult smoking. DNA methylation levels were analysed in relation to body mass index (BMI), waist circumference (WC), fasting glucose (FG), high-density lipoprotein cholesterol (HDL—C), triglycerides (TG), diastolic, and systolic blood pressure (BP).FindingsLower DNA methylation at three out of eight GFI1-CpGs was associated with exposure to maternal prenatal smoking, whereas, all eight CpGs were associated with adult own smoking. Lower DNA methylation at cg14179389, the strongest maternal prenatal smoking locus, was associated with increased WC and BP when adjusted for sex, age, and adult smoking with Bonferroni-corrected P < 0·012. In contrast, lower DNA methylation at cg09935388, the strongest adult own smoking locus, was associated with decreased BMI, WC, and BP (adjusted 1 × 10−7 < P < 0.01). Similarly, lower DNA methylation at cg12876356, cg18316974, cg09662411, and cg18146737 was associated with decreased BMI and WC (5 × 10−8 < P < 0.001). Lower DNA methylation at all the CpGs was consistently associated with higher TG levels.InterpretationEpigenetic changes at the GFI1 were linked to smoking exposure in-utero/in-adulthood and robustly associated with cardio-metabolic risk factors.
Takeuchi F, Akiyama M, Matoba N, et al., 2018, Interethnic analyses of blood pressure loci in populations of East Asian and European descent., Nature Communications, Vol: 9, ISSN: 2041-1723
Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, we perform a multi-stage genome-wide association study for BP (max N = 289,038) principally in East Asians and meta-analysis in East Asians and Europeans. We report 19 new genetic loci and ancestry-specific BP variants, conforming to a common ancestry-specific variant association model. At 10 unique loci, distinct non-rare ancestry-specific variants colocalize within the same linkage disequilibrium block despite the significantly discordant effects for the proxy shared variants between the ethnic groups. The genome-wide transethnic correlation of causal-variant effect-sizes is 0.898 and 0.851 for systolic and diastolic BP, respectively. Some of the ancestry-specific association signals are also influenced by a selective sweep. Our results provide new evidence for the role of common ancestry-specific variants and natural selection in ethnic differences in complex traits such as BP.
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