Risk of diabetes in siblings of index cases with Type 2 diabetes: implications for genetic studies

Weijnen, Catherine F.; Rich, Stephen S.; Meigs, James B.; Królewski, Andrzej S.; Warram, James H.

doi:10.1046/j.1464-5491.2002.00624.x

Cited by 100 publications

(78 citation statements)

References 44 publications

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“…This is because the 20 loci identified by GWA studies have small λ s values (Table 3), with a λ s value in combination of only about 1.08-1.10. The expected λ s value for type 2 diabetes appears to be somewhere between 1.2 and 6 [96,[117][118][119][120]. Therefore, we must conclude that much of the genetic cause of type 2 diabetes remains unidentified and the GWA results should be seen as complementing, not replacing, the linkage analyses.…”

Section: Discussionmentioning

confidence: 97%

Agreement among type 2 diabetes linkage studies but a poor correlation with results from genome-wide association studies

Lillioja

Wilton

2009

Diabetologia

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Aims/hypothesis Little of the genetic basis for type 2 diabetes has been explained, despite numerous genetic linkage studies and the discovery of multiple genes in genome-wide association (GWA) studies. To begin to resolve the genetic component of this disease, we searched for sites at which genetic results had been corroborated in different studies, in the expectation that replication among studies should direct us to the genomic locations of causative genes with more confidence than the results of individual studies. Methods We have mapped the physical location of results from 83 linkage reports (for type 2 diabetes and diabetes precursor quantitative traits [QTs, e.g. plasma insulin levels]) and recent large GWA reports (for type 2 diabetes) onto the same human genome sequence to identify replicated results in diabetes genetic 'hot spots'. Results Genetic linkage has been found at least ten times at 18 different locations, and at least five times in 56 locations. All replication clusters contained study populations from more than one ethnic background and most contained results for both diabetes and QTs. There is no close relationship between the GWA results and linkage clusters, and the nine best replication clusters have no nearby GWA result. Conclusions/interpretation Many of the genes for type 2 diabetes remain unidentified. This analysis identifies the broad location of yet to be identified genes on 6q, 1q, 18p, 2q, 20q, 17pq, 8p, 19q and 9q. The discrepancy between the linkage and GWA studies may be explained by the presence of multiple, uncommon, mildly deleterious polymorphisms scattered throughout the regulatory and coding regions of genes for type 2 diabetes.

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Section: Discussionmentioning

confidence: 97%

Agreement among type 2 diabetes linkage studies but a poor correlation with results from genome-wide association studies

Lillioja

Wilton

2009

Diabetologia

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“…The similarity in r g can be taken to indicate that only a portion of the genes that contribute to BMI and type 2 diabetes mellitus are the same. While the ratio of the risk of type 2 diabetes in siblings of patients with the disease compared with disease risk in the general population has varied between 3 and 4 [18], genome-wide association studies have estimated the λ attributable to all loci for type 2 diabetes to be only little above one, i.e. these loci have been estimated to explain 5 to 10% of the inherited predisposition [19].…”

Section: Discussionmentioning

confidence: 99%

“…The long follow-up of a population-based twin cohort in our study also enabled coverage of the near-life-time risk of type 2 diabetes, hence improving the possibility of detecting diabetes cases that would have remained unnoticed in a cross sectional set-up. The prospective study design, moreover, enabled us to steer clear of problems of information loss due to study participants not attending follow-up visits, as has been the case for most cohort studies of type 2 diabetes incidence [18]. Thus, the combination of a large population-based twin sample, together with the nationwide diabetes medication register, provides at least as reliable tools for the study of type 2 diabetes epidemiology as any of the smaller scale studies using direct measurement of blood glucose values.…”

Section: Discussionmentioning

confidence: 99%

Evidence that BMI and type 2 diabetes share only a minor fraction of genetic variance: a follow-up study of 23,585 monozygotic and dizygotic twins from the Finnish Twin Cohort Study

et al. 2010

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Aims/hypothesis We investigated whether BMI predicts type 2 diabetes in twins and to what extent that is explained by common genetic factors. Methods This was a population-based twin cohort study. Monozygotic (n=4,076) and dizygotic (n=9,109) nondiabetic twin pairs born before 1958 answered a questionnaire in 1975, from which BMI was obtained. Information on incident cases of diabetes was obtained by linkage to nationwide registers until 2005. Results Altogether, 1,332 twins (6.3% of men, 5.1% of women) developed type 2 diabetes. The HR for type 2 diabetes increased monotonically with a mean of 1.22 (95% CI 1.20-1.24) per BMI unit and of 1.97 (95% CI 1.87-2.08) per SD of BMI. The HRs for lean, overweight, obese and morbidly obese participants were 0.59, 2.96, 6.80 and 13.64 as compared with normal weight participants. Model heritability estimates for bivariate variance due to an additive genetic component and non-shared environmental component were 75% (men) and 71% (women) for BMI, and 73% and 64%, respectively for type 2 diabetes. The correlations between genetic variance components (r g ) indicated that one fifth of the covariance of BMI and type 2 diabetes was due to shared genetic influences. Although the mean monozygotic concordance for type 2 diabetes was approximately twice the dizygotic one, age of onset of diabetes within twin pair members varied greatly, irrespective of zygosity. Conclusions/interpretation A 28-year follow-up of adult Finnish twins showed that despite high trait heritability estimates, only a fraction of covariation in BMI and incident type 2 diabetes was of genetic origin.

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“…The highest risk in firstdegree relatives, compared to the general population, persists even after removal from the family of origin, for example, as a result of adoption. Furthermore, in identical monozygotic twins (with identical genetic makeup), the concordance rate for the disease approaches 100%, much higher than that seen in non-identical (dizygotic) twins or among siblings [7] . Genetic predisposition in T2DM is also supported by the observation that differences in disease prevalence rates exist among populations, even after migration of entire ethnic groups to another country, thus independent from the environmental influences [8] .…”

Section: Topic Highlightmentioning

confidence: 99%

Recent advances in the molecular genetics of type 2 diabetes mellitus

Brunetti¹,

Chiefari²,

Foti³

2014

WJD

106

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Type 2 diabetes mellitus (T2DM) is a complex disease in which both genetic and environmental factors interact in determining impaired β-cell insulin secretion and peripheral insulin resistance. Insulin resistance in muscle, liver and fat is a prominent feature of most patients with T2DM and obesity, resulting in a reduced response of these tissues to insulin. Considerable evidence has been accumulated to indicate that heredity is a major determinant of insulin resistance and T2DM. It is believed that, among individuals destined to develop T2DM, hyperinsulinemia is the mechanism by which the pancreatic β-cell initially compensates for deteriorating peripheral insulin sensitivity, thus ensuring normal glucose tolerance. Most of these people will develop T2DM when β-cells fail to compensate. Despite the progress achieved in this field in recent years, the genetic causes of insulin resistance and T2DM remain elusive. Candidate gene association, linkage and genome-wide association studies have highlighted the role of genetic factors in the development of T2DM. Using these strategies, a large number of variants have been identified in many of these genes, most of which may influence both hepatic and peripheral insulin resistance, adipogenesis and β-cell mass and function. Recently, a new Key words: Genome-wide association study; Candidate gene; Genetic variants; High-mobility group A1; Insulin resistant diabetes Core tip: Despite the progress in clinical and laboratory investigations, the fundamental cause of type 2 diabetes mellitus (T2DM) remains uncertain. Candidate gene, linkage and genome-wide association studies have highlighted the role of genetics in the development of T2DM. Using these strategies, a large number of variants have been identified in many genes, most of which may influence an individual's risk of developing T2DM. In this review, we compile information on genetic factors that influence the risk of T2DM. In addition, we discuss the results from recent studies on the role of HMGA1 on the issue, which might be important for future breakthroughs in this field.Brunetti A, Chiefari E, Foti D. Recent advances in the molecular genetics of type 2 diabetes mellitus. World J Diabetes 2014; 5(2

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Risk of diabetes in siblings of index cases with Type 2 diabetes: implications for genetic studies

Abstract: The selection of families with non-obese index cases and vertical transmission of diabetes through three generations may improve the success of efforts to map susceptibility genes for Type 2 diabetes.

Cited by 100 publications

References 44 publications

Agreement among type 2 diabetes linkage studies but a poor correlation with results from genome-wide association studies

Agreement among type 2 diabetes linkage studies but a poor correlation with results from genome-wide association studies

Evidence that BMI and type 2 diabetes share only a minor fraction of genetic variance: a follow-up study of 23,585 monozygotic and dizygotic twins from the Finnish Twin Cohort Study

Recent advances in the molecular genetics of type 2 diabetes mellitus

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