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The genetic architecture of type 2 diabetes
Fuchsberger, Christian,Flannick, Jason,Teslovich, Tanya M,Mahajan, Anubha,Agarwala, Vineeta,Gaulton, Kyle J,Ma, Clement,Fontanillas, Pierre,Moutsianas, Loukas,McCarthy, Davis J,Rivas, Manuel A,Perry, Macmillan Journals ltd., etc.] 2016 Nature Vol.536 No.7614
<P>The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of heritability. To test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole genome sequencing in 2,657 Europeans with and without diabetes, and exome sequencing in a total of 12,940 subjects from five ancestral groups. To increase statistical power, we expanded sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support a major role for lower-frequency variants in predisposition to type 2 diabetes.</P>
Common Variants in Mendelian Kidney Disease Genes and Their Association with Renal Function
Parsa, Afshin,Fuchsberger, Christian,Kö,ttgen, Anna,O’Seaghdha, Conall M.,Pattaro, Cristian,de Andrade, Mariza,Chasman, Daniel I.,Teumer, Alexander,Endlich, Karlhans,Olden, Matthias,Chen, Ming-Hue American Society of Nephrology 2013 Journal of the American Society of Nephrology Vol.24 No.12
Evaluating the contribution of rare variants to type 2 diabetes and related traits using pedigrees
Jun, Goo,Manning, Alisa,Almeida, Marcio,Zawistowski, Matthew,Wood, Andrew R.,Teslovich, Tanya M.,Fuchsberger, Christian,Feng, Shuang,Cingolani, Pablo,Gaulton, Kyle J.,Dyer, Thomas,Blackwell, Thomas W. National Academy of Sciences 2018 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.115 No.2
<P>A major challenge in evaluating the contribution of rare variants to complex disease is identifying enough copies of the rare alleles to permit informative statistical analysis. To investigate the contribution of rare variants to the risk of type 2 diabetes (T2D) and related traits, we performed deep whole-genome analysis of 1,034 members of 20 large Mexican-American families with high prevalence of T2D. If rare variants of large effect accounted for much of the diabetes risk in these families, our experiment was powered to detect association. Using gene expression data on 21,677 transcripts for 643 pedigree members, we identified evidence for large-effect rare-variant c/s-expression quantitative trait loci that could not be detected in population studies, validating our approach. Flowever, we did not identify any rare variants of large effect associated with T2D, or the related traits of fasting glucose and insulin, suggesting that large-effect rare variants account for only a modest fraction of the genetic risk of these traits in this sample of families. Reliable identification of large-effect rare variants will require larger samples of extended pedigrees or different study designs that further enrich for such variants.</P>
Loss-of-function mutations in SLC30A8 protect against type 2 diabetes
Flannick, Jason,Thorleifsson, Gudmar,Beer, Nicola L,Jacobs, Suzanne B R,Grarup, Niels,Burtt, Noë,l P,Mahajan, Anubha,Fuchsberger, Christian,Atzmon, Gil,Benediktsson, Rafn,Blangero, John,Bowden, Do Nature Pub. Co 2014 Nature genetics Vol.46 No.4
Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ∼150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10<SUP>−6</SUP>), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (−0.17 s.d., P = 4.6 × 10<SUP>−4</SUP>). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.