Parental origin of sequence variants associated with complex diseases

Kong, Augustine; Steinthórsdóttir, Valgerður; Másson, Gísli; Þorleifsson, Guðmar; Sulem, Patrick; Besenbacher, Søren; Jónasdóttir, Áslaug; Sigurðsson, Ásgeir; Kristinsson, Kári; Jónasdóttir, Aðalbjörg; Frigge, Michael L.; Gylfason, Arnaldur; Olason, Pall I.; Gudjonsson, Sigurjon A.; Sverrisson, Sverrir T.; Stacey, Simon; Sigurgeirsson, Bárður; Benediktsdóttir, Kristrún R.; Sigurðsson, Helgi; Jónsson, Þorvaldur; Benediktsson, Rafn; Ólafsson, Jón; Jóhannsson, Óskar T.; Hreiðarsson, Ástráður B.; Sigurðsson, Gunnar; Ferguson‐Smith, Anne C.; Guðbjartsson, Daníel F.; Þorsteinsdóttir, Unnur; Stefánsson, Kári

doi:10.1038/nature08625

Cited by 519 publications

(486 citation statements)

References 23 publications

(26 reference statements)

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“…Interestingly, sex-specific parental effects were strongest for cholesterol concentrations. Thereby, these findings using an alternative way of analysing data support our previous findings of sexspecific parent-of-origin effects for many traits [11] and also justify similar analyses for genetic variants influencing these traits [36].…”

Section: Discussionsupporting

confidence: 86%

Heritability and familiality of type 2 diabetes and related quantitative traits in the Botnia Study

Almgren

Lehtovirta

Isomaa³

et al. 2011

Diabetologia

215

162

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Aims/hypothesis To study the heritability and familiality of type 2 diabetes and related quantitative traits in families from the Botnia Study in Finland. Methods Heritability estimates for type 2 diabetes adjusted for sex, age and BMI are provided for different age groups of type 2 diabetes and for 34 clinical and metabolic traits in 5,810 individuals from 942 families using a variance component model (SOLAR). In addition, family means of these traits and their distribution across families are calculated. Results The strongest heritability for type 2 diabetes was seen in patients with age at onset 35-60 years (h 2 =0.69). However, In contrast, physical activity showed rather low heritability (0.16-0.18), whereas smoking showed strong heritability (0.57-0.59). Family means of these traits differed two-to fivefold between families belonging to the lowest and highest quartile of the trait (p<0.00001). Conclusions/interpretation To detect stronger genetic effects in type 2 diabetes, it seems reasonable to restrict inclusion of patients to those with age at onset 35-60 years. Sequencing of families with extreme quantitative traits could be an important next step in the dissection of the genetics of type 2 diabetes.

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Section: Discussionsupporting

confidence: 86%

Heritability and familiality of type 2 diabetes and related quantitative traits in the Botnia Study

Almgren

Lehtovirta

Isomaa³

et al. 2011

Diabetologia

215

162

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“…These studies did not analyse incident diabetes separately in men and women or in relation to a paternal and/or maternal diabetes transmission. Kong et al [10] emphasize the importance of parental origin in complex diseases: an allele may be protective when inherited from one parent but be a risk allele when inherited from the other parent.…”

Section: Discussionmentioning

confidence: 99%

Transmission of Type 2 diabetes to sons and daughters: the D.E.S.I.R. cohort

et al. 2017

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Aims To document the family transmission of Type 2 diabetes to men and women.Method The French D.E.S.I.R. cohort followed men and women over 9 years, with 3-yearly testing for incident Type 2 diabetes. First-and/or second-degree family histories of diabetes were available for 2187 men and 2282 women. Ageadjusted hazard ratios were estimated for various family members and groupings of family members, as well as for a genetic diabetes risk score, based on 65 diabetes-associated loci.Results Over 9 years, 136 men and 63 women had incident Type 2 diabetes. The hazard ratios for diabetes associated with having a first-degree family member with diabetes (parents, siblings, children) differed between men [1.21 (95% CI 0.80, 1.85)] and women [3.02 (95% CI 1.83, 4.99); P interaction =0.006]. The genetic risk score was predictive of diabetes in both men and women, with similar hazard ratios 1.10 (95% CI 1.06, 1.15) and 1.08 (95% CI 1.02, 1.14) respectively, for each additional at-risk allele. In women, the risk associated with having a family member with diabetes persisted after adjusting for the genetic score.Conclusion Women with a family history of diabetes (paternal or maternal) were at risk of developing Type 2 diabetes and this risk was independent of a genetic score; in contrast, for men, there was no association. Diabetes screening and prevention may need to more specifically target women with diabetes in their family, but further studies are required as the number of people with diabetes in this study was small. Diabet. Med. 34, 1615-1622 (2017 IntroductionThe transmission of Type 2 diabetes within the family is well established. In the Framingham Offspring Study, the odds ratios for offspring to have diabetes were 3.5 or 3.4 if the father or the mother has diabetes, respectively, and 6.1 if both have diabetes [1]; in the European InterAct study, these hazard ratios were 3.17 and 2.88 respectively, and 5.14 if both parents have diabetes [2].As discussed by Meigs et al.[1], some studies, but not all, have shown that diabetes is maternally rather than paternally transmitted; however, few studies have assessed family transmission according to the sex of the index case. In the InterAct study, the hazard ratios associated with a firstdegree family history of diabetes were 2.64 for men and 2.77 for women, essentially identical [2]. By contrast, in two cross-sectional studies of people with Type 2 diabetes, more women than men had a parental transmission of diabetes [3,4].In the present study, we analyzed incident diabetes in men and women according to the presence of diabetes in first-and second-degree family members, and in particular in their father and their mother. The impact of a genetic risk score with 65 diabetes-related loci and maternal transmission of diabetes was also investigated. Methods Study populationThe present cohort study used data from the Epidemiological Study on Insulin Resistance syndrome (D.E.S.I.R.) including 1994-1996 [5]. Participants were recruited from volunteers attending free-of...

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“…So far, genome-wide association studies (GWAS) and subsequent meta-analysis have identified 23 validated risk loci influencing risk of type 2 diabetes [1][2][3]. While many common gene variants have shown an influence on estimates of beta cell function, only few variants have an impact on insulin resistance [2,[4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Variants at DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B loci are associated with reduced glucose-stimulated beta cell function in middle-aged Danish people

et al. 2010

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Aims/hypothesis A meta-analysis of 21 genome-wide association studies identified 11 novel genetic loci implicated in fasting glucose homeostasis. We aimed to evaluate the impact of these variants on insulin release and insulin sensitivity estimated from OGTTs. Methods Eleven variants in or near DGKB/TMEM195, ADCY5, MADD, ADRA2A, FADS1, CRY2, SLC2A2, GLIS3, PROX1, C2CD4B and IGF1 were genotyped in 6,784 middle-aged participants of the population-based Inter99 cohort. Association studies of quantitative estimates of insulin release and insulin sensitivity were performed in 5,722 non-diabetic Danish participants on whom an OGTT was performed.Results Assuming an additive genetic model, carriers of the alleles increasing fasting glucose in DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B showed decreased glucosestimulated insulin release as assessed by the BIGTT-acute insulin response index (2.7-3.5%; p<0.005 for all) and by corrected insulin response (2.8-5.9%; p<0.03 for all). In addition, the PROX1 glucose-raising allele showed a 2.9% decreased corrected insulin response (p=0.03), while the hyperglycaemic allele of variants in or near ADRA2A, FADS1, CRY2 and C2CD4B were associated with a 2.6% to T. W. Boesgaard and N. Grarup contributed equally to this work. Diabetologia (2010) 53:1647-1655 DOI 10.1007/s00125-010-1753 9.3% decrease in one or both of two different OGTT-based disposition indices (p<0.02 for all). After correction for multiple testing, variants in the DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B loci were associated with estimates of beta cell function. Conclusions/interpretation We found that the lead variants at the DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B loci were associated with decreased glucose-stimulated insulin response. This association underlines the importance of pancreatic beta cell dysfunction in the genetic predisposition to hyperglycaemia and type 2 diabetes.

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Parental origin of sequence variants associated with complex diseases

Cited by 519 publications

References 23 publications

Heritability and familiality of type 2 diabetes and related quantitative traits in the Botnia Study

Heritability and familiality of type 2 diabetes and related quantitative traits in the Botnia Study

Transmission of Type 2 diabetes to sons and daughters: the D.E.S.I.R. cohort

Variants at DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B loci are associated with reduced glucose-stimulated beta cell function in middle-aged Danish people

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