| 1. |
- Saxena, Richa, et al.
(författare)
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Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:2, s. 142-148
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Tidskriftsartikel (refereegranskat)abstract
- Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958–30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, β (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 × 10−15). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 × 10−17; ratio of insulin to glucose area under the curve, P = 1.3 × 10−16) and diminished incretin effect (n = 804; P = 4.3 × 10−4). We also identified variants at ADCY5 (rs2877716, P = 4.2 × 10−16), VPS13C (rs17271305, P = 4.1 × 10−8), GCKR (rs1260326, P = 7.1 × 10−11) and TCF7L2 (rs7903146, P = 4.2 × 10−10) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09–1.15, P = 4.8 × 10−18).
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| 2. |
- Dai, Qile, et al.
(författare)
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OTTERS: a powerful TWAS framework leveraging summary-level reference data
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Most existing TWAS tools require individual-level eQTL reference data and thus are not applicable to summary-level reference eQTL datasets. The development of TWAS methods that can harness summary-level reference data is valuable to enable TWAS in broader settings and enhance power due to increased reference sample size. Thus, we develop a TWAS framework called OTTERS (Omnibus Transcriptome Test using Expression Reference Summary data) that adapts multiple polygenic risk score (PRS) methods to estimate eQTL weights from summary-level eQTL reference data and conducts an omnibus TWAS. We show that OTTERS is a practical and powerful TWAS tool by both simulations and application studies.
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| 3. |
- Keller, Maria, et al.
(författare)
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THOC5 : A novel gene involved in HDL-cholesterol metabolism
- 2013
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Ingår i: Journal of Lipid Research. - 0022-2275. ; 54:11, s. 3170-3176
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Tidskriftsartikel (refereegranskat)abstract
- Although numerous genes are known to regulate serum lipid traits, identified variants explain only a small proportion of the expected heritability. We intended to identify further genetic variants associated with lipid phenotypes in a self-contained population of Sorbs in Germany. We performed a genome-wide association study (GWAS) on LDL-cholesterol, HDL-cholesterol (HDL-C), and triglyceride (TG) levels in 839 Sorbs. All single-nucleotide polymorphisms with a P value <0.01 were subjected to a meta-analysis, including an independent Swedish cohort (Diabetes Genetics Initiative; n = ∼ 3,100). Novel association signals with the strongest effects were subjected to replication studies in an additional German cohort (Berlin, n = 2,031). In the initial GWAS in the Sorbs, we identified 14 loci associated with lipid phenotypes reaching P values <10 -5 and confirmed significant effects for 18 previously reported loci. The combined meta-analysis of the three study cohorts (n(HDL) = 6041; n (LDL) = 5,995; n(TG) = 6,087) revealed a novel association for a variant in THOC5 (rs8135828) with serum HDL-C levels (P = 1.78 × 10-7; Z -score = -5.221). Consistently, the variant was also associated with circulating APOA1 levels in Sorbs. The small interfering RNA-mediated mRNA silencing of THOC5 in HepG2 cells resulted in lower mRNA levels of APOA1, SCARB1, and ABCG8 (all P < 0.05). We propose THOC5 to be a novel gene involved in the regulation of serum HDL-C levels.
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| 4. |
- Mardinoglu, Adil, et al.
(författare)
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Extensive weight loss reveals distinct gene expression changes in human subcutaneous and visceral adipose tissue
- 2015
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Weight loss has been shown to significantly improve Adipose tissue (AT) function, however changes in AT gene expression profiles particularly in visceral AT (VAT) have not been systematically studied. Here, we tested the hypothesis that extensive weight loss in response to bariatric surgery (BS) causes AT gene expression changes, which may affect energy and lipid metabolism, inflammation and secretory function of AT. We assessed gene expression changes by whole genome expression chips in AT samples obtained from six morbidly obese individuals, who underwent a two step BS strategy with sleeve gastrectomy as initial and a Roux-en-Y gastric bypass as second step surgery after 12 +/- 2 months. Global gene expression differences in VAT and subcutaneous (S) AT were analyzed through the use of genome-scale metabolic model (GEM) for adipocytes. Significantly altered gene expressions were PCR-validated in 16 individuals, which also underwent a two-step surgery intervention. We found increased expression of cell death-inducing DFFA-like effector a (CIDEA), involved in formation of lipid droplets in both fat depots in response to significant weight loss. We observed that expression of the genes associated with metabolic reactions involved in NAD+, glutathione and branched chain amino acid metabolism are significantly increased in AT depots after surgery-induced weight loss.
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| 5. |
- Toenjes, Anke, et al.
(författare)
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Genetic variation in GPR133 is associated with height: genome wide association study in the self-contained population of Sorbs
- 2009
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 18:23, s. 4662-4668
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Tidskriftsartikel (refereegranskat)abstract
- Recently, associations of several common genetic variants with height have been reported in different populations. We attempted to identify further variants associated with adult height in a self-contained population (the Sorbs in Eastern Germany) as discovery set. We performed a genome wide association study (GWAS) (similar to 390 000 genetic polymorphisms, Affymetrix gene arrays) on adult height in 929 Sorbian individuals. Subsequently, the best SNPs (P < 0.001) were taken forward to a meta-analysis together with two independent cohorts [Diabetes Genetics Initiative, British 1958 Birth Cohort, (58BC, publicly available)]. Furthermore, we genotyped our best signal for replication in two additional German cohorts (Leipzig, n = 1044 and Berlin, n = 1728). In the primary Sorbian GWAS, we identified 5 loci with a P-value < 10(-5) and 455 SNPs with P-value < 0.001. In the meta-analysis on those 455 SNPs, only two variants in GPR133 (rs1569019 and rs1976930; in LD with each other) retained a P-value at or below 10(-6) and were associated with height in the three cohorts individually. Upon replication, the SNP rs1569019 showed significant effects on height in the Leipzig cohort (P = 0.004, beta = 1.166) and in 577 men of the Berlin cohort (P = 0.049, beta = 1.127) though not in women. The combined analysis of all five cohorts (n = 6,687) resulted in a P-value of 4.7 x 10(-8) (beta = 0.949). In conclusion, our GWAS suggests novel loci influencing height. In view of the robust replication in five different cohorts, we propose GPR133 to be a novel gene associated with adult height.
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| 6. |
- Tönjes, Anke, et al.
(författare)
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Genome-wide meta-analysis identifies novel determinants of circulating serum progranulin
- 2018
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 27:3, s. 546-558
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Tidskriftsartikel (refereegranskat)abstract
- Progranulin is a secreted protein with important functions in processes including immune and inflammatory response, metabolism and embryonic development. The present study aimed at identification of genetic factors determining progranulin concentrations. We conducted a genome-wide association meta-analysis for serum progranulin in three independent cohorts from Europe: Sorbs (N=848) and KORA (N=1628) from Germany and PPP-Botnia (N=335) from Finland (total N=2811). Single nucleotide polymorphisms (SNPs) associated with progranulin levels were replicated in two additional German cohorts: LIFE-Heart Study (Leipzig; N=967) and Metabolic Syndrome Berlin Potsdam (Berlin cohort; N=833). We measured mRNA expression of genes in peripheral blood mononuclear cells (PBMC) by micro-arrays and performed mRNA expression quantitative trait and expression-progranulin association studies to functionally substantiate identified loci. Finally, we conducted siRNA silencing experiments in vitro to validate potential candidate genes within the associated loci. Heritability of circulating progranulin levels was estimated at 31.8% and 26.1% in the Sorbs and LIFE-Heart cohort, respectively. SNPs at three loci reached study-wide significance (rs660240 in CELSR2-PSRC1-MYBPHL-SORT1, rs4747197 in CDH23- PSAP and rs5848 in GRN) explaining 19.4%/15.0% of the variance and 61%/57% of total heritability in the Sorbs/LIFE-Heart Study. The strongest evidence for association was at rs660240 (P=5.75x10-50), which was also associated with mRNA expression of PSRC1 in PBMC (P=1.51x10-21). Psrc1 knockdown in murine preadipocytes led to a consecutive 30% reduction in progranulin secretion. In conclusion, the present meta-GWAS combined with mRNA expression identified three loci associated with progranulin and supports the role of PSRC1 in the regulation of progranulin secretion.
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