A Genome Scan for Type 2 Diabetes Susceptibility Loci in a Genetically Isolated Population
Author:
Permutt Marshall A.1, Wasson Jonathon C.1, Suarez Brian K.2, Lin Jennifer2, Thomas Jeffrey3, Meyer Joanne4, Lewitzky Steve4, Rennich Jean S.4, Parker Alex4, DuPrat Laura4, Maruti Sanchit4, Chayen Susan5, Glaser Benjamin5
Affiliation:
1. Division of Metabolism, Endocrinology, and Diabetes and the 2. Department of Psychiatry, Washington University Medical School, St. Louis, Missouri 3. Parke-Davis Pharmaceutical Research, Ann Arbor, Michigan 4. Millennium Pharmaceuticals, Cambridge, Massachusetts 5. Department of Endocrinology and Metabolism, Hebrew University, Hadassah Medical Center, Jerusalem, Israel
Abstract
A total of 896 individuals of Ashkenazi Jewish descent were ascertained in Israel from 267 multiplex families, including 472 sib-pairs affected with type 2 diabetes. A genome-wide scan with average marker spacing of 9.5 cM revealed five regions on four chromosomes (4q, 8q, 14q, and 20q) that exhibited nominal evidence for linkage (P < 0.05). The highest observed nonparametric linkage Z score was 2.41 (equivalent to a logarithm of odds score of 1.26) at marker D4S1501. A maximal signal, with a Z score of 2.05, was observed on chromosome 20 near marker D20S195, and another on 20p near marker D20S103 (Z 1.80). A single marker on chromosome 8 (D8S593) and two adjacent markers on chromosome 14 (D14S749 and D14S605) also attained evidence of linkage. To explore the hypothesis that the signals on chromosomes 4 and 20 are differentially attributable to variation in BMI or age of onset, an ordered subset analysis was conducted. This analysis revealed that only when the families were ranked by BMI (in increasing order) did a subset attain nominal significance, and only for chromosome 4. The findings reported here lend credence to the hypothesis, now supported by four studies of Caucasian populations and most recently by a combined analysis of 1,852 pedigrees, that a type 2 diabetes susceptibility locus resides on chromosome 20q. This population, because of its unique genetic attributes, may facilitate identification of this and other genes contributing to type 2 diabetes.
Publisher
American Diabetes Association
Subject
Endocrinology, Diabetes and Metabolism,Internal Medicine
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