| 1. |
- Fadista, João, et al.
(author)
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LoFtool : a gene intolerance score based on loss-of-function variants in 60 706 individuals
- 2017
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In: Bioinformatics. - : Oxford University Press (OUP). - 1367-4803 .- 1367-4811. ; 33:4, s. 471-474
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Journal article (peer-reviewed)abstract
- MOTIVATION: Depletion of loss-of-function (LoF) mutations may provide a rank of genic functional intolerance and consequently susceptibility to disease.RESULTS: Here we have studied LoF mutations in 60 706 unrelated individuals and show that the most intolerant quartile of ranked genes is enriched in rare and early onset diseases and explains 87% of de novo haploinsufficient OMIM mutations, 17% more than any other gene scoring tool. We detected particular enrichment in expression of the depleted LoF genes in brain (odds ratio = 1.5; P-value = 4.2e-07). By searching for de novo haploinsufficient mutations putatively associated with neurodevelopmental disorders in four recent studies, we were able to explain 81% of them. Taken together, this study provides a novel gene intolerance ranking system, called LoFtool, which may help in ranking genes of interest based on their LoF intolerance and tissue expression.AVAILABILITY AND IMPLEMENTATION: The LoFtool gene scores are available in the Supplementary data CONTACT: joaofadista@gmail.comSupplementary information: Supplementary data are available at Bioinformatics online.
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| 2. |
- Flannick, Jason, et al.
(author)
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Data Descriptor : Sequence data and association statistics from 12,940 type 2 diabetes cases and controls
- 2017
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In: Scientific Data. - : Springer Science and Business Media LLC. - 2052-4463. ; 4
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Journal article (peer-reviewed)abstract
- To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (> 80% of low-frequency coding variants in similar to ~82 K Europeans via the exome chip, and similar to ~90% of low-frequency non-coding variants in similar to ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.
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| 3. |
- Manning, Alisa, et al.
(author)
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A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
- 2017
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In: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 66:7, s. 2019-2032
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Journal article (peer-reviewed)abstract
- To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.
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| 4. |
- Ottosson-Laakso, Emilia, et al.
(author)
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Glucose-induced Changes in Gene Expression in Human Pancreatic Islets - Causes or Consequences of Chronic Hyperglycemia
- 2017
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In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 66:12, s. 3013-3028
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Journal article (peer-reviewed)abstract
- Dysregulation of gene expression in islets from type 2 diabetic patients might be causally involved in the development of hyperglycemia or it could develop as a consequence of hyperglycemia, i.e. glucotoxicity. To separate the genes potentially causally involved in pathogenesis from those likely to be secondary to the hyperglycemia we exposed islets from human donors to normal or high glucose concentrations for 24 hours and analyzed gene expression. We compared these findings with gene expression in islets from donors with normal glucose tolerance (NGT) and hyperglycemia (HG, including T2D). The genes whose expression changed in the same direction after short-term glucose exposure as in T2D were considered most likely to be a consequence of hyperglycemia. Genes whose expression changed in HG but not after short-term glucose exposure, in particular genes that also correlated with insulin secretion, were considered the strongest candidates for causal involvement in T2D. E.g. ERO1LB, DOCK10, IGSF11 and PRR14L were down-regulated in HG and correlated positively with insulin secretion suggesting a protective role while TMEM132C was up-regulated in HG and correlated negatively with insulin secretion suggesting a potential pathogenic role.This study provides a catalogue of gene expression changes in human pancreatic islets after exposure to glucose.
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| 5. |
- Sandholm, Niina, et al.
(author)
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The genetic landscape of renal complications in type 1 diabetes
- 2017
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In: Journal of the American Society of Nephrology. - 1046-6673. ; 28:2, s. 557-574
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Journal article (peer-reviewed)abstract
- Diabetes is the leading cause of ESRD. Despite evidence for a substantial heritability of diabetic kidney disease, efforts to identify genetic susceptibility variants have had limited success. We extended previous efforts in three dimensions, examining a more comprehensive set of genetic variants in larger numbers of subjects with type 1 diabetes characterized for a wider range of cross-sectional diabetic kidney disease phenotypes. In 2843 subjects, we estimated that the heritability of diabetic kidney disease was 35% (P=6.4310-3). Genome-wide association analysis and replication in 12,540 individuals identified no single variants reaching stringent levels of significance and, despite excellent power, provided little independent confirmation of previously published associatedvariants.Whole-exome sequencing in 997 subjects failed to identify any large-effect coding alleles of lower frequency influencing the risk of diabetic kidney disease. However, sets of alleles increasing body mass index (P=2.2310-5) and the risk of type 2 diabetes (P=6.1310-4) associated with the risk of diabetic kidney disease.Wealso found genome-wide genetic correlation between diabetic kidney disease and failure at smoking cessation (P=1.1310-4). Pathway analysis implicated ascorbate and aldarate metabolism (P=9.0310-6), and pentose and glucuronate interconversions (P=3.0310-6) in pathogenesis of diabetic kidney disease. These data provide further evidence for the role of genetic factors influencing diabetic kidney disease in those with type 1 diabetes and highlight some key pathways that may be responsible. Altogether these results reveal important biology behind the major cause of kidney disease.
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