| 21. |
- de Vries, Paul S., et al.
(författare)
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Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions
- 2019
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Ingår i: American Journal of Epidemiology. - : Oxford University Press. - 0002-9262 .- 1476-6256. ; 188:6, s. 1033-1054
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Tidskriftsartikel (refereegranskat)abstract
- 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 x 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 x 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.
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| 22. |
- Ding, Ming, et al.
(författare)
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Dairy consumption, systolic blood pressure, and risk of hypertension : Mendelian randomization study
- 2017
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Ingår i: The BMJ. - : BMJ Publishing Group Ltd. - 1756-1833 .- 0959-8138. ; 356
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE To examine whether previous observed inverse associations of dairy intake with systolic blood pressure and risk of hypertension were causal. DESIGN Mendelian randomization study using the single nucleotide polymorphism rs4988235 related to lactase persistence as an instrumental variable. SETTING CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium. PARTICIPANTS Data from 22 studies with 171 213 participants, and an additional 10 published prospective studies with 26 119 participants included in the observational analysis. MAIN OUTCOME MEASURES The instrumental variable estimation was conducted using the ratio of coefficients approach. Using metaanalysis, an additional eight published randomized clinical trials on the association of dairy consumption with systolic blood pressure were summarized. RESULTS Compared with the CC genotype (CC is associated with complete lactase deficiency), the CT/TT genotype (TT is associated with lactose persistence, and CT is associated with certain lactase deficiency) of LCT-13910 (lactase persistence gene) rs4988235 was associated with higher dairy consumption (0.23 (about 55 g/day), 95% confidence interval 0.17 to 0.29) serving/day; P<0.001) and was not associated with systolic blood pressure (0.31, 95% confidence interval -0.05 to 0.68 mm Hg; P=0.09) or risk of hypertension (odds ratio 1.01, 95% confidence interval 0.97 to 1.05; P=0.27). Using LCT-13910 rs4988235 as the instrumental variable, genetically determined dairy consumption was not associated with systolic blood pressure (beta=1.35, 95% confidence interval -0.28 to 2.97 mm Hg for each serving/day) or risk of hypertension (odds ratio 1.04, 0.88 to 1.24). Moreover, meta-analysis of the published clinical trials showed that higher dairy intake has no significant effect on change in systolic blood pressure for interventions over one month to 12 months (intervention compared with control groups: beta=-0.21, 95% confidence interval -0.98 to 0.57 mm Hg). In observational analysis, each serving/day increase in dairy consumption was associated with -0.11 (95% confidence interval -0.20 to -0.02 mm Hg; P=0.02) lower systolic blood pressure but not risk of hypertension (odds ratio 0.98, 0.97 to 1.00; P=0.11). CONCLUSION The weak inverse association between dairy intake and systolic blood pressure in observational studies was not supported by a comprehensive instrumental variable analysis and systematic review of existing clinical trials.
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| 23. |
- Evangelou, Evangelos, et al.
(författare)
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Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:10, s. 1412-1425
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Tidskriftsartikel (refereegranskat)abstract
- High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
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| 24. |
- Feitosa, Mary F., et al.
(författare)
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Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries
- 2018
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Ingår i: PLOS ONE. - : Public library science. - 1932-6203. ; 13:6
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Tidskriftsartikel (refereegranskat)abstract
- Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in approximate to 131 K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P <1.0 x 10(-5)). In Stage 2, these SNVs were tested for independent external replication in individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10(-8)). For African ancestry samples, we detected 18 potentially novel BP loci (P< 5.0 x 10(-8)) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2 have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
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| 25. |
- Hibar, Derrek P., et al.
(författare)
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Novel genetic loci associated with hippocampal volume
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
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| 26. |
- Huang, Tao, et al.
(författare)
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Dairy Consumption and Body Mass Index Among Adults : Mendelian Randomization Analysis of 184802 Individuals from 25 Studies
- 2018
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 64:1, s. 183-191
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Associations between dairy intake and body mass index (BMI) have been inconsistently observed in epidemiological studies, and the causal relationship remains ill defined.METHODS: We performed Mendelian randomization (MR) analysis using an established dairy intake-associated genetic polymorphism located upstream of the lactase gene (LCT-13910 C/T, rs4988235) as an instrumental variable (IV). Linear regression models were fitted to analyze associations between (a) dairy intake and BMI, (b) rs4988235 and dairy intake, and (c) rs4988235 and BMI in each study. The causal effect of dairy intake on BMI was quantified by IV estimators among 184802 participants from 25 studies.RESULTS: Higher dairy intake was associated with higher BMI (β = 0.03 kg/m2 per serving/day; 95% CI, 0.00–0.06; P = 0.04), whereas the LCT genotype with 1 or 2 T allele was significantly associated with 0.20 (95% CI, 0.14–0.25) serving/day higher dairy intake (P = 3.15 × 10−12) and 0.12 (95% CI, 0.06–0.17) kg/m2 higher BMI (P = 2.11 × 10−5). MR analysis showed that the genetically determined higher dairy intake was significantly associated with higher BMI (β = 0.60 kg/m2 per serving/day; 95% CI, 0.27–0.92; P = 3.0 × 10−4).CONCLUSIONS: The present study provides strong evidence to support a causal effect of higher dairy intake on increased BMI among adults.
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| 27. |
- Mahajan, Anubha, et al.
(författare)
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Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation
- 2022
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:5, s. 560-572
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Tidskriftsartikel (refereegranskat)abstract
- We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 x 10(-9)), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background. Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.
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| 28. |
- Mahajan, Anubha, et al.
(författare)
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Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes
- 2018
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:4, s. 559-571
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Tidskriftsartikel (refereegranskat)abstract
- We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10−7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent ‘false leads’ with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.
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| 29. |
- Meng, Weihua, et al.
(författare)
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A genome-wide association study suggests new evidence for an association of the NADPH Oxidase 4 (NOX4) gene with severe diabetic retinopathy in type 2 diabetes
- 2018
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Ingår i: Acta Ophthalmologica. - : Wiley. - 1755-375X. ; 96:7, s. 811-819
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Diabetic retinopathy is the most common eye complication in patients with diabetes. The purpose of this study is to identify genetic factors contributing to severe diabetic retinopathy. Methods: A genome-wide association approach was applied. In the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) datasets, cases of severe diabetic retinopathy were defined as type 2 diabetic patients who were ever graded as having severe background retinopathy (Level R3) or proliferative retinopathy (Level R4) in at least one eye according to the Scottish Diabetic Retinopathy Grading Scheme or who were once treated by laser photocoagulation. Controls were diabetic individuals whose longitudinal retinopathy screening records were either normal (Level R0) or only with mild background retinopathy (Level R1) in both eyes. Significant Single Nucleotide Polymorphisms (SNPs) were taken forward for meta-analysis using multiple Caucasian cohorts. Results: Five hundred and sixty cases of type 2 diabetes with severe diabetic retinopathy and 4,106 controls were identified in the GoDARTS cohort. We revealed that rs3913535 in the NADPH Oxidase 4 (NOX4) gene reached a p value of 4.05 × 10−9. Two nearby SNPs, rs10765219 and rs11018670 also showed promising p values (p values = 7.41 × 10−8 and 1.23 × 10−8, respectively). In the meta-analysis using multiple Caucasian cohorts (excluding GoDARTS), rs10765219 and rs11018670 showed associations for diabetic retinopathy (p = 0.003 and 0.007, respectively), while the p value of rs3913535 was not significant (p = 0.429). Conclusion: This genome-wide association study of severe diabetic retinopathy suggests new evidence for the involvement of the NOX4 gene.
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| 30. |
- Merino, Jordi, et al.
(författare)
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Quality of dietary fat and genetic risk of type 2 diabetes : individual participant data meta-analysis
- 2019
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Ingår i: BMJ. British Medical Journal. - : BMJ Publishing Group Ltd. - 0959-8146 .- 0959-535X. ; 366
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE To investigate whether the genetic burden of type 2 diabetes modifies the association between the quality of dietary fat and the incidence of type 2 diabetes.DESIGN Individual participant data meta-analysis.DATA SOURCES Eligible prospective cohort studies were systematically sourced from studies published between January 1970 and February 2017 through electronic searches in major medical databases (Medline, Embase, and Scopus) and discussion with investigators.REVIEW METHODS Data from cohort studies or multicohort consortia with available genome-wide genetic data and information about the quality of dietary fat and the incidence of type 2 diabetes in participants of European descent was sought. Prospective cohorts that had accrued five or more years of follow-up were included. The type 2 diabetes genetic risk profile was characterized by a 68-variant polygenic risk score weighted by published effect sizes. Diet was recorded by using validated cohort-specific dietary assessment tools. Outcome measures were summary adjusted hazard ratios of incident type 2 diabetes for polygenic risk score, isocaloric replacement of carbohydrate (refined starch and sugars) with types of fat, and the interaction of types of fat with polygenic risk score.RESULTS Of 102 305 participants from 15 prospective cohort studies, 20 015 type 2 diabetes cases were documented after a median follow-up of 12 years (interquartile range 9.4-14.2). The hazard ratio of type 2 diabetes per increment of 10 risk alleles in the polygenic risk score was 1.64 (95% confidence interval 1.54 to 1.75, I-2 = 7.1%, tau(2) = 0.003). The increase of polyunsaturated fat and total omega 6 polyunsaturated fat intake in place of carbohydrate was associated with a lower risk of type 2 diabetes, with hazard ratios of 0.90 (0.82 to 0.98, I-2 = 18.0%, tau(2) = 0.006; per 5% of energy) and 0.99 (0.97 to 1.00, I-2 = 58.8%, tau(2) = 0.001; per increment of 1 g/d), respectively. Increasing monounsaturated fat in place of carbohydrate was associated with a higher risk of type 2 diabetes (hazard ratio 1.10, 95% confidence interval 1.01 to 1.19, I-2 = 25.9%, tau(2) = 0.006; per 5% of energy). Evidence of small study effects was detected for the overall association of polyunsaturated fat with the risk of type 2 diabetes, but not for the omega 6 polyunsaturated fat and monounsaturated fat associations. Significant interactions between dietary fat and polygenic risk score on the risk of type 2 diabetes (P>0.05 for interaction) were not observed.CONCLUSIONS These data indicate that genetic burden and the quality of dietary fat are each associated with the incidence of type 2 diabetes. The findings do not support tailoring recommendations on the quality of dietary fat to individual type 2 diabetes genetic risk profiles for the primary prevention of type 2 diabetes, and suggest that dietary fat is associated with the risk of type 2 diabetes across the spectrum of type 2 diabetes genetic risk.
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