| 1. |
- Shungin, Dmitry, et al.
(författare)
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New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
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Tidskriftsartikel (refereegranskat)abstract
- Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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| 2. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 3. |
- 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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| 4. |
- Berndt, Sonja I., et al.
(författare)
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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69
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Tidskriftsartikel (refereegranskat)abstract
- Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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| 5. |
- Pattaro, Cristian, et al.
(författare)
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Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
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| 6. |
- Chasman, Daniel I., et al.
(författare)
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Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function
- 2012
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 21:24, s. 5329-5343
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Tidskriftsartikel (refereegranskat)abstract
- In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P 5.6 10(9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 10(4)2.2 10(7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.
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| 7. |
- Kilpeläinen, Tuomas O, et al.
(författare)
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Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
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| 8. |
- Speliotes, Elizabeth K., et al.
(författare)
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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| 9. |
- Gorski, Mathias, et al.
(författare)
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Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies
- 2022
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Ingår i: Kidney International. - : Elsevier. - 0085-2538 .- 1523-1755. ; 102:3, s. 624-639
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Tidskriftsartikel (refereegranskat)abstract
- Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genomewide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR- baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant- by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with agedependency of genetic cross- section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in- silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03- 1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.
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| 10. |
- Nikpay, Majid, et al.
(författare)
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A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease
- 2015
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:10, s. 1121-1121
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Tidskriftsartikel (refereegranskat)abstract
- Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of similar to 185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.
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