| 1. |
- Wuttke, Matthias, et al.
(författare)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry 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.
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| 2. |
- 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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| 3. |
- Surendran, Praveen, et al.
(författare)
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Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
- 2020
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 52:12, s. 1314-1332
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Tidskriftsartikel (refereegranskat)abstract
- 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 similar 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 x 10(-8)), 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 similar to 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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| 4. |
- Gorski, Mathias, et al.
(författare)
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Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline
- 2021
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Ingår i: Kidney International. - : Elsevier. - 0085-2538 .- 1523-1755. ; 99:4, s. 926-939
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Tidskriftsartikel (refereegranskat)abstract
- Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
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| 5. |
- Roselli, Carolina, et al.
(författare)
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Multi-ethnic genome-wide association study for atrial fibrillation
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:9, s. 1225-1233
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Tidskriftsartikel (refereegranskat)abstract
- Atrial fibrillation (AF) affects more than 33 million individuals worldwide(1) and has a complex heritability(2). We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.
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| 6. |
- van Zuydam, NR, et al.
(författare)
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A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes
- 2018
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 67:7, s. 1414-1427
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Tidskriftsartikel (refereegranskat)abstract
- Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10−8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.
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| 7. |
- Sammalisto, S, et al.
(författare)
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A male-specific quantitative trait locus on 1p21 controlling human stature
- 2005
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Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 42:12, s. 932-939
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Tidskriftsartikel (refereegranskat)abstract
- Background: Many genome-wide scans aimed at complex traits have been statistically underpowered due to small sample size. Combining data from several genome-wide screens with comparable quantitative phenotype data should improve statistical power for the localisation of genomic regions contributing to these traits. Objective: To perform a genome-wide screen for loci affecting adult stature by combined analysis of four previously performed genome-wide scans. Methods: We developed a web based computer tool, Cartographer, for combining genetic marker maps which positions genetic markers accurately using the July 2003 release of the human genome sequence and the deCODE genetic map. Using Cartographer, we combined the primary genotype data from four genome-wide scans and performed variance components (VC) linkage analyses for human stature on the pooled dataset of 1417 individuals from 277 families and performed VC analyses for males and females separately. Results: We found significant linkage to stature on 1p21 (multipoint LOD score 4.25) and suggestive linkages on 9p24 and 18q21 (multipoint LOD scores 2.57 and 2.39, respectively) in males-only analyses. We also found suggestive linkage to 4q35 and 22q13 (multipoint LOD scores 2.18 and 2.85, respectively) when we analysed both females and males and to 13q12 (multipoint LOD score 2.66) in females-only analyses. Conclusions: We strengthened the evidence for linkage to previously reported quantitative trait loci (QTL) for stature and also found significant evidence of a novel male-specific QTL on 1p21. Further investigation of several interesting candidate genes in this region will help towards characterisation of this first sex-specific locus affecting human stature.
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| 8. |
- Florez, JC, et al.
(författare)
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Association testing in 9,000 people fails to confirm the association of the insulin receptor substrate-1 G972R polymorphism with type 2 diabetes
- 2004
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 53:12, s. 3313-3318
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Tidskriftsartikel (refereegranskat)abstract
- The insulin receptor substrate (IRS)-1 is an important component of the insulin signal transduction cascade. Several reports suggest that a Gly-->Arg change in codon 972 is associated with type 2 diabetes and related traits, and a recent meta-analysis reported a modest but nominally significant association with type 2 diabetes (odds ratio [OR] 1.25 in favor of carriers of the Arg allele [95% CI 1.05-1.48). To test the reproducibility of the model in a recent meta-analysis, we examined genotype-phenotype correlation in three large Caucasian samples (not previously reported for this variant) totaling 9,000 individuals (estimated to have >95% power to obtain a P<0.05 for the OR of 1.25 estimated in the meta-analysis). In our combined sample, comprising 4,279 case and 3,532 control subjects, as well as 1,189 siblings discordant for type 2 diabetes, G972R was not associated with type 2 diabetes (OR 0.96 [0.84-1.10], P = 0.60). Genotype at G972R had no significant effect on various measures of insulin secretion or insulin resistance in a set of Scandinavian samples in whom we had detailed phenotypic data. In contrast, the well-documented associations of peroxisome proliferator-activated receptor gamma P12A and Kir6.2 E23K with type 2 diabetes are both robustly observed in these 9,000 subjects, including an additional (previously unpublished) confirmation of Kir6.2 E23K and type 2 diabetes in the Polish and North American samples (combined OR 1.15 [1.05-1.261, P = 0.001). Despite genotyping 9,000 people and >95% power to reproduce the estimated OR from the recent meta-analysis, we were unable to replicate the association of the IRS-1 G972R polymorphism with type 2 diabetes.
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| 9. |
- Fredriksson, Jenny, et al.
(författare)
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Variation in GYS1 Interacts with Exercise and Gender to Predict Cardiovascular Mortality
- 2007
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 2:3
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Tidskriftsartikel (refereegranskat)abstract
- Background. The muscle glycogen synthase gene (GYS1) has been associated with type 2 diabetes (T2D), the metabolic syndrome (MetS), male myocardial infarction and a defective increase in muscle glycogen synthase protein in response to exercise. We addressed the questions whether polymorphism in GYS1 can predict cardiovascular (CV) mortality in a high-risk population, if this risk is influenced by gender or physical activity, and if the association is independent of genetic variation in nearby apolipoprotein E gene (APOE). Methodology/Principal Findings. Polymorphisms in GYS1 (XbaIC>T) and APOE (-219G>T, epsilon 2/epsilon 3/epsilon 4) were genotyped in 4,654 subjects participating in the Botnia T2D-family study and followed for a median of eight years. Mortality analyses were performed using Cox proportional-hazards regression. During the follow-up period, 749 individuals died, 409 due to CV causes. In males the GYS1 XbaI T-allele (hazard ratio (HR) 1.9 [1.2-2.9]), T2D (2.5 [1.7-3.8]), earlier CV events (1.7 [1.2-2.5]), physical inactivity (1.9 [1.2-2.9]) and smoking (1.5 [1.0-2.3]) predicted CV mortality. The GYS1 XbaI T-allele predicted CV mortality particularly in physically active males (HR 1.7 [1.3-2.0]). Association of GYS1 with CV mortality was independent of APOE (219TT/epsilon 4), which by its own exerted an effect on CV mortality risk in females (2.9 [1.9-4.4]). Other independent predictors of CV mortality in females were fasting plasma glucose (1.2 [1.1-1.2]), high body mass index (BMI) (1.0 [1.0-1.1]), hypertension (1.9 [1.2-3.1]), earlier CV events (1.9 [1.3-2.8]) and physical inactivity (1.9 [1.2-2.8]). Conclusions/Significance. Polymorphisms in GYS1 and APOE predict CV mortality in T2D families in a gender-specific fashion and independently of each other. Physical exercise seems to unmask the effect associated with the GYS1 polymorphism, rendering carriers of the variant allele less susceptible to the protective effect of exercise on the risk of CV death, which finding could be compatible with a previous demonstration of defective increase in the glycogen synthase protein in carriers of this polymorphism.
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| 10. |
- Hamrefors, Viktor, et al.
(författare)
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A gene score of nine LDL and HDL regulating genes is associated with fluvastatin induced cholesterol changes in women.
- 2010
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Ingår i: Journal of Lipid Research. - 1539-7262. ; 51:3, s. 625-634
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Tidskriftsartikel (refereegranskat)abstract
- While conventional pharmacogenetic studies have considered single gene effects, we tested if a genetic score of nine LDL- and HDL-associated SNPs, previously shown to predict cardiovascular disease, is related to fluvastatin induced lipid change. In patients with asymptomatic plaque in the right carotid artery, thus candidates for statin therapy, we related Score LDL (APOB(rs693), APOE(rs4420638), HMGCR(rs12654264), LDLR(rs1529729) and PCSK9(rs11591147) and score HDL (ABCA1(rs3890182), CETP(rs1800775), LIPC(rs1800588) and LPL(rs328) ) as well as the combined score LDL+HDL to fluvastatin induced LDL reduction (+/- metoprolol) (n=395) and HDL increase (n=187) following one year fluvastatin treatment. In women, increasing number of unfavorable alleles (i.e. alleles conferring higher LDL and lower HDL) of score LDL+HDL (P=0,037) and of score LDL (P=0,023) was associated with less pronounced fluvastatin induced LDL reduction. Furthermore, in women both score LDL+HDL (P=0,001) and score HDL (P=0,022) was directly correlated with more pronounced fluvastatin induced HDL increase, explaining 5,9-11,6 % of the variance in treatment response in women. There were no such associations in men. This suggests that a gene score based on variation in nine different LDL and HDL associated genes is of importance for the magnitude of fluvastatin HDL increase in women with asymptomatic plaque in the carotid artery.
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