Dataset Information

Increased frequency of rare missense PPP1R3B variants among Danish patients with type 2 diabetes.

ABSTRACT: BACKGROUND:PPP1R3B has been suggested as a candidate gene for monogenic forms of diabetes as well as type 2 diabetes (T2D) due to its association with glycaemic trait and its biological role in glycogen synthesis. OBJECTIVES:To study if rare missense variants in PPP1R3B increase the risk of maturity onset diabetes of the young (MODY), T2D or affect measures of glucose metabolism. METHOD:Targeted resequencing of PPP1R3B was performed in 8,710 samples; MODY patients with unknown etiology (n = 54), newly diagnosed patients with T2D (n = 2,930) and population-based control individuals (n = 5,726, of whom n = 4,569 had normal glucose tolerance). All population-based sampled individuals were examined using an oral glucose tolerance test. RESULTS:Among n = 396 carriers, we identified twenty-three PPP1R3B missense mutations, none of which segregated with MODY. The burden of likely deleterious PPP1R3B variants was significantly increased with a total of 17 carriers among patients with T2D (0.58% (95% CI: 0.36-0.93)) compared to 18 carriers among non-diabetic individuals (0.31% (95% CI: 0.20-0.49)), resulting in an increased risk of T2D (OR (95% CI) = 2.57 (1.14-5.79), p = 0.02 (age and sex adjusted)). Furthermore, carriers with diabetes had less abdominal fat and a higher serum concentration of LDL-cholesterol compared to patients with T2D without rare missense PPP1R3B variants. In addition, non-diabetic carriers had a higher birth weight compared to non-carriers. CONCLUSION:Rare missense PPP1R3B variants may predispose to T2D.

SUBMITTER: Niazi RK

PROVIDER: S-EPMC6328241 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Increased frequency of rare missense PPP1R3B variants among Danish patients with type 2 diabetes.

Niazi Robina Khan RK Sun Jihua J Have Christian Theil CT Hollensted Mette M Linneberg Allan A Pedersen Oluf O Nielsen Jens Steen JS Rungby Jørgen J Grarup Niels N Hansen Torben T Gjesing Anette Prior AP

PloS one 20190110 1

<h4>Background</h4>PPP1R3B has been suggested as a candidate gene for monogenic forms of diabetes as well as type 2 diabetes (T2D) due to its association with glycaemic trait and its biological role in glycogen synthesis.<h4>Objectives</h4>To study if rare missense variants in PPP1R3B increase the risk of maturity onset diabetes of the young (MODY), T2D or affect measures of glucose metabolism.<h4>Method</h4>Targeted resequencing of PPP1R3B was performed in 8,710 samples; MODY patients with unkn ...[more]

PMID: 30629617

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Project description:In recent years, DISC1 has emerged as one of the most credible and best supported candidate genes for schizophrenia and related neuropsychiatric disorders. Furthermore, increasing evidence--both genetic and functional--indicates that many of its protein interaction partners are also involved in the development of these diseases. In this study, we applied a pooled sample 454 sequencing strategy, to explore the contribution of genetic variation in DISC1 and 10 of its interaction partners (ATF5, Grb2, FEZ1, LIS-1, PDE4B, NDE1, NDEL1, TRAF3IP1, YWHAE, and ZNF365) to schizophrenia susceptibility in an isolated northern Swedish population. Mutation burden analysis of the identified variants in a population of 486 SZ patients and 514 control individuals, revealed that non-synonymous rare variants with a MAF<0.01 were significantly more present in patients compared to controls (8.64% versus 4.7%, P?=?0.018), providing further evidence for the involvement of DISC1 and some of its interaction partners in psychiatric disorders. This increased burden of rare missense variants was even more striking in a subgroup of early onset patients (12.9% versus 4.7%, P?=?0.0004), highlighting the importance of studying subgroups of patients and identifying endophenotypes. Upon investigation of the potential functional effects associated with the identified missense variants, we found that ?90% of these variants reside in intrinsically disordered protein regions. The observed increase in mutation burden in patients provides further support for the role of the DISC1 pathway in schizophrenia. Furthermore, this study presents the first evidence supporting the involvement of mutations within intrinsically disordered protein regions in the pathogenesis of psychiatric disorders. As many important biological functions depend directly on the disordered state, alteration of this disorder in key pathways may represent an intriguing new disease mechanism for schizophrenia and related neuropsychiatric diseases. Further research into this unexplored domain will be required to elucidate the role of the identified variants in schizophrenia etiology.

Dataset Information

Increased frequency of rare missense PPP1R3B variants among Danish patients with type 2 diabetes.

Publications

Increased frequency of rare missense PPP1R3B variants among Danish patients with type 2 diabetes.

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