Copyright © 2003 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 73, Issue 2, 323-335, 1 August 2003
doi:10.1086/377139
Localization of a Susceptibility Gene for Type 2 Diabetes to Chromosome 5q34–q35.2
Inga Reynisdottir1, 
, 
, Gudmar Thorleifsson1, Rafn Benediktsson2, 3, , Gunnar Sigurdsson2, 3, Valur Emilsson1, Anna Sigurlin Einarsdottir1, Eyrun Edda Hjorleifsdottir1, Gudbjorg Th. Orlygsdottir1, Gudrun Thora Bjornsdottir2, Jona Saemundsdottir1, Skarphedinn Halldorsson1, Soffia Hrafnkelsdottir1, Steinunn Bjorg Sigurjonsdottir1, Svana Steinsdottir1, Mitchell Martin4, Jarema P. Kochan4, Brian K. Rhees4, Struan F.A. Grant1, Michael L. Frigge1, Augustine Kong1, Vilmundur Gudnason2, Kari Stefansson1, * and Jeffrey R. Gulcher1, *
1 deCODE Genetics, Landspitali-University Hospital, Reykjavik
2 Icelandic Heart Association, Landspitali-University Hospital, Reykjavik
3 Landspitali-University Hospital, Reykjavik
4 Hoffmann-La Roche, Nutley, NJ
Address for correspondence and reprints: Dr. Inga Reynisdottir, deCODE Genetics, Inc., Sturlugata 8, 101 Reykjavik, Iceland. or Dr. Rafn Benediktsson, Icelandic Heart Association, Holtasmari 1, 201 Kopavogur, Iceland* These authors contributed equally to this work.
Abstract
We report a genomewide linkage study of type 2 diabetes (T2D [MIM 125853]) in the Icelandic population. A list of type 2 diabetics was cross-matched with a computerized genealogical database clustering 763 type 2 diabetics into 227 families. The diabetic patients and their relatives were genotyped with 906 microsatellite markers. A nonparametric multipoint linkage analysis yielded linkage to 5q34–q35.2 (LOD = 2.90, P=1.29×10−4) in all diabetics. Since obesity, here defined as body mass index (BMI) ⩾30 kg/m2, is a key risk factor for the development of T2D, we studied the data either independently of BMI or by stratifying the patient group as obese (BMI ⩾30) or nonobese (BMI <30). A nonparametric multipoint linkage analysis yielded linkage to 5q34–q35.2 (LOD = 3.64, P=2.12×10−5) in the nonobese diabetics. No linkage was observed in this region for the obese diabetics. Linkage analysis conditioning on maternal transmission to the nonobese diabetics resulted in a LOD score of 3.48 (P=3.12×10−5) in the same region, whereas conditioning on paternal transmission led to a substantial drop in the LOD score. Finally, we observed potential interactions between the 5q locus and two T2D susceptibility loci, previously mapped in other populations.
Article Information
PubMed
Related Articles
- On the Replication of Genetic Associations: Timing Can Be Ev...On the Replication of Genetic Associations: Timing Can Be Everything!
The American Journal of Human Genetics, Volume 82, Issue 4, 11 April 2008, Pages 849-858
Jessica Lasky-Su, Helen N. Lyon, Valur Emilsson, Iris M. Heid, Cliona Molony, Benjamin A. Raby, Ross Lazarus, Barbara Klanderman, Manuel E. Soto-Quiros, Lydiana Avila, Edwin K. Silverman, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Florian Kronenberg, Caren Vollmert, Thomas Illig, Caroline S. Fox, Daniel Levy, Nan Laird, Xiao Ding, Matt B. McQueen, Johannah Butler, Kristin Ardlie, Constantina Papoutsakis, George Dedoussis, Christopher J. O'Donnell, H.-Erich Wichmann, Juan C. Celedón, Eric Schadt, Joel Hirschhorn, Scott T. Weiss, Kari Stefansson and Christoph Lange
AbstractThe failure of researchers to replicate genetic-association findings is most commonly attributed to insufficient statistical power, population stratification, or various forms of between-study heterogeneity or environmental influences. Here, we illustrate another potential cause for nonreplications that has so far not received much attention in the literature. We illustrate that the strength of a genetic effect can vary by age, causing “age-varying associations.” If not taken into account during the design and the analysis of a study, age-varying genetic associations can cause nonreplication. By using the 100K SNP scan of the Framingham Heart Study, we identified an age-varying association between a SNP in ROBO1 and obesity and hypothesized an age-gene interaction. This finding was followed up in eight independent samples comprising 13,584 individuals. The association was replicated in five of the eight studies, showing an age-dependent relationship (one-sided combined p = 3.92 × 10−9, combined p value from pediatric cohorts = 2.21 × 10−8, combined p value from adult cohorts = 0.00422). Furthermore, this study illustrates that it is difficult for cross-sectional study designs to detect age-varying associations. If the specifics of age- or time-varying genetic effects are not considered in the selection of both the follow-up samples and in the statistical analysis, important genetic associations may be missed.
Abstract | | - A Susceptibility Gene for Psoriatic Arthritis Maps to Chromo...A Susceptibility Gene for Psoriatic Arthritis Maps to Chromosome 16q: Evidence for Imprinting
The American Journal of Human Genetics, Volume 72, Issue 1, 1 January 2003, Pages 125-131
Ari Karason, Johann E. Gudjonsson, Ruchi Upmanyu, Arna A. Antonsdottir, Valdimar B. Hauksson, E. Hjaltey Runasdottir, Hjortur H. Jonsson, Daniel F. Gudbjartsson, Michael L. Frigge, Augustine Kong, Kari Stefansson, Helgi Valdimarsson and Jeffrey R. Gulcher
AbstractSeveral genetic loci have been reported for psoriasis, but none has been specifically linked to psoriatic arthritis (PsA), a condition that affects >10% of patients with psoriasis. A genetic component for PsA is suggested by segregation within families and high concordance among identical twins. We performed a linkage scan to map genes contributing to PsA. We identified 178 patients with PsA out of 906 patients who were included in our genetic study of psoriasis. Using a comprehensive genealogy database, we were able to connect 100 of these into 39 families. We genotyped the patients using a framework marker set of 1,000 microsatellite markers, with an average density of 3 cM, and performed multipoint, affected-only, allele-sharing linkage analysis using the Allegro program. On the basis of the initial results, we genotyped more markers for the most prominent loci. A linkage with a LOD score of 2.17 was observed on chromosome 16q. The linkage analysis, conditioned on paternal transmission to affected individuals, gave a LOD score of 4.19, whereas a LOD score of only 1.03 was observed when conditioned for maternal transmission. A suggestive locus on chromosome 16q has previously been implicated in psoriasis. Our data indicate that a gene at this locus may be involved in paternal transmission of PsA.
Abstract | | - Possible Genomic Imprinting of Three Human Obesity–Related G...Possible Genomic Imprinting of Three Human Obesity–Related Genetic Loci
The American Journal of Human Genetics, Volume 76, Issue 3, 1 March 2005, Pages 427-437
Chuanhui Dong, Wei-Dong Li, Frank Geller, Lei Lei, Ding Li, Olga Y. Gorlova, Johannes Hebebrand, Christopher I. Amos, Robert D. Nicholls and R. Arlen Price
AbstractTo detect potentially imprinted, obesity-related genetic loci, we performed genomewide parent-of-origin linkage analyses under an allele-sharing model for discrete traits and under a family regression model for obesity-related quantitative traits, using a European American sample of 1,297 individuals from 260 families, with 391 microsatellite markers. We also used two smaller, independent samples for replication (a sample of 370 German individuals from 89 families and a sample of 277 African American individuals from 52 families). For discrete-trait analysis, we found evidence for a maternal effect in chromosome region 10p12 across the three samples, with LOD scores of 5.69 (single-point) and 4.52 (multipoint) for the pooled sample. For quantitative-trait analysis, we found the strongest evidence for a maternal effect (single-point LOD of 2.85; multipoint LOD of 4.01 for body mass index [BMI] and 3.69 for waist circumference) in region 12q24 and for a paternal effect (single-point LOD of 4.79; multipoint LOD of 3.72 for BMI) in region 13q32, in the European American sample. The results suggest that parent-of-origin effects, perhaps including genomic imprinting, may play a role in human obesity.
Abstract | | - …more
