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Genomewide search for type 2 diabetes susceptibility genes in four American populations.

ABSTRACT: Type 2 diabetes is a serious, genetically influenced disease for which no fully effective treatments are available. Identification of biochemical or regulatory pathways involved in the disease syndrome could lead to innovative therapeutic interventions. One way to identify such pathways is the genetic analysis of families with multiple affected members where disease predisposing genes are likely to be segregating. We undertook a genomewide screen (389-395 microsatellite markers) in samples of 835 white, 591 Mexican American, 229 black, and 128 Japanese American individuals collected as part of the American Diabetes Association's GENNID study. Multipoint nonparametric linkage analyses were performed with diabetes, and diabetes or impaired glucose homeostasis (IH). Linkage to diabetes or IH was detected near markers D5S1404 (map position 77 cM, LOD = 2.80), D12S853 (map position 82 cM, LOD = 2.81) and GATA172D05 (X-chromosome map position 130 cM, LOD = 2.99) in whites, near marker D3S2432 (map position 51 cM, LOD = 3.91) in Mexican Americans, and near marker D10S1412 (map position 14 cM, LOD = 2.39) in African Americans mainly collected in phase 1 of the study. Further analyses showed evidence for interactions between the chromosome 5 locus and region on chromosome 12 containing the MODY 3 gene (map position 132 cM) and between the X-chromosome locus and region near D12S853 (map position 82 cM) in whites. Although these results were not replicated in samples collected in phase 2 of the GENNID study, the region on chromosome 12 was replicated in samples from whites described by Bektas et al. (1999).

SUBMITTER: Ehm MG

PROVIDER: S-EPMC1378057 | biostudies-other | 2000 Jun

REPOSITORIES: biostudies-other

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Genomewide search for type 2 diabetes susceptibility genes in four American populations.

Ehm M G MG Karnoub M C MC Sakul H H Gottschalk K K Holt D C DC Weber J L JL Vaske D D Briley D D Briley L L Kopf J J McMillen P P Nguyen Q Q Reisman M M Lai E H EH Joslyn G G Shepherd N S NS Bell C C Wagner M J MJ Burns D K DK

American journal of human genetics 20000502 6

Type 2 diabetes is a serious, genetically influenced disease for which no fully effective treatments are available. Identification of biochemical or regulatory pathways involved in the disease syndrome could lead to innovative therapeutic interventions. One way to identify such pathways is the genetic analysis of families with multiple affected members where disease predisposing genes are likely to be segregating. We undertook a genomewide screen (389-395 microsatellite markers) in samples of 83 ...[more]

PMID: 10793009

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Project description:ObjectivesGenome-wide association studies (GWAS) have identified >100 loci independently contributing to type 2 diabetes (T2D) risk. However, translational implications for precision medicine and for the development of novel treatments have been disappointing, due to poor knowledge of how these loci impact T2D pathophysiology. Here, we aimed to measure the expression of genes located nearby T2D associated signals and to assess their effect on insulin secretion from pancreatic beta cells.MethodsThe expression of 104 candidate T2D susceptibility genes was measured in a human multi-tissue panel, through PCR-free expression assay. The effects of the knockdown of beta-cell enriched genes were next investigated on insulin secretion from the human EndoC-βH1 beta-cell line. Finally, we performed RNA-sequencing (RNA-seq) so as to assess the pathways affected by the knockdown of the new genes impacting insulin secretion from EndoC-βH1, and we analyzed the expression of the new genes in mouse models with altered pancreatic beta-cell function.ResultsWe found that the candidate T2D susceptibility genes' expression is significantly enriched in pancreatic beta cells obtained by laser capture microdissection or sorted by flow cytometry and in EndoC-βH1 cells, but not in insulin sensitive tissues. Furthermore, the knockdown of seven T2D-susceptibility genes (CDKN2A, GCK, HNF4A, KCNK16, SLC30A8, TBC1D4, and TCF19) with already known expression and/or function in beta cells changed insulin secretion, supporting our functional approach. We showed first evidence for a role in insulin secretion of four candidate T2D-susceptibility genes (PRC1, SRR, ZFAND3, and ZFAND6) with no previous knowledge of presence and function in beta cells. RNA-seq in EndoC-βH1 cells with decreased expression of PRC1, SRR, ZFAND6, or ZFAND3 identified specific gene networks related to T2D pathophysiology. Finally, a positive correlation between the expression of Ins2 and the expression of Prc1, Srr, Zfand6, and Zfand3 was found in mouse pancreatic islets with altered beta-cell function.ConclusionsThis study showed the ability of post-GWAS functional studies to identify new genes and pathways involved in human pancreatic beta-cell function and in T2D pathophysiology.

Project description:Given that early-onset type 2 diabetes mellitus (T2DM), metabolic syndrome (MetS), and hyperuricemia have been shown to have strong genetic components, the statistical power of a genetic association study may be increased by focusing on early-onset subjects with these conditions. Although genome-wide association studies have identified various genes and loci significantly associated with T2DM, MetS, and hyperuricemia, genetic variants that contribute to predisposition to these conditions in Japanese subjects remain to be identified definitively. We performed exome-wide association studies (EWASs) for early-onset T2DM, MetS, or hyperuricemia to identify genetic variants that confer susceptibility to these conditions. A total of 8,102 individuals aged ≤65 years were enrolled in the present study. The EWAS for T2DM was performed with 7,407 subjects (1,696 cases, 5,711 controls), that for MetS with 4,215 subjects (2,296 cases, 1,919 controls), and that for hyperuricemia with 7,919 subjects (1,365 cases, 6,554 controls). Single nucleotide polymorphisms (SNPs) were genotyped with Illumina Human Exome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. The relationship of allele frequencies for 31,210, 31,521, or 31,142 SNPs that passed quality control for T2DM, MetS, or hyperuricemia, respectively, was examined with Fisher's exact test. To compensate for multiple comparisons of genotypes with T2DM, MetS, or hyperuricemia, we applied Bonferroni's correction for statistical significance of association. The EWAS of allele frequencies revealed that four, six, or nine SNPs were significantly associated with T2DM (P<1.60×10-6), MetS (P<1.59×10-6), or hyperuricemia (P<1.61×10-6), respectively. Multivariable logistic regression analysis with adjustment for age and sex revealed that three, six, or nine SNPs were significantly related to T2DM (P<0.0031), MetS (P<0.0021), or hyperuricemia (P<0.0014). After examination of the association of identified SNPs to T2DM-, MetS-, or hyperuricemia-related traits, linkage disequilibrium of the SNPs, and results of previous genome-wide association studies, newly identified ZNF860 and OR4F6 were the susceptibility loci for T2DM, OR52E4 and OR4F6 for MetS, and HERPUD2 for hyperuricemia. Given that OR4F6 was significantly associated with both T2DM and MetS, we newly identified four genes (ZNF860, OR4F6, OR52E4, HERPUD2) that confer susceptibility to early-onset T2DM, MetS, or hyperuricemia. Determination of genotypes for the SNPs in these genes may prove informative for assessment of the genetic risk for T2DM, MetS, or hyperuricemia.

Dataset Information

Genomewide search for type 2 diabetes susceptibility genes in four American populations.

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Genomewide search for type 2 diabetes susceptibility genes in four American populations.

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