A Gene Conferring Susceptibility to Type 2 Diabetes in Conjunction With Obesity Is Located on Chromosome 18p11
- Alex Parker1,
- Joanne Meyer1,
- Steve Lewitzky1,
- Jean S. Rennich1,
- Gayun Chan1,
- Jeffrey D. Thomas2,
- Marju Orho-Melander3,
- Mikko Lehtovirta3,
- Carol Forsblom3,
- Auli Hyrkkö3,
- Martin Carlsson3,
- Cecilia Lindgren3 and
- Leif C. Groop3
- 1From Millennium Pharmaceuticals, Cambridge, Massachusetts
- 2Parke-Davis Pharmaceutical Research, Ann Arbor, Michigan
- 3Department of Endocrinology, Wallenberg Laboratory, Malmö University Hospital, University of Lund, Malmö, Sweden
Abstract
Genome-wide nonparametric linkage analysis of 480 sib-pairs affected with type 2 diabetes revealed linkage to a previously unreported susceptibility locus on chromosome 18p11. This result improved with stringent subphenotyping using age- and sex-adjusted BMI, ultimately reaching a logarithm of odds of 3.82 (allele sharing 0.6654) at a point between markers D18S976 and D18S391 when the most obese 20% of the sample was analyzed. Several genes on chromosome 18 have been suggested as metabolic disease candidates, but none of these colocalize with our linkage result. We conclude that our results provide support for the presence of a currently uncharacterized gene on chromosome 18p, certain alleles of which confer increased susceptibility to type 2 diabetes in conjunction with obesity. We additionally observed moderate evidence for linkage to chromosome 1, near marker D1S3462; chromosome 4, near marker D4S2361; chromosome 5, near marker D5S1505; and chromosome 17, near marker D17S1301.
- AGE, age at onset of type 2 diabetes
- ASP, affected sib-pair
- CEPH, Centre d’Etude du Polymorphisme Humain
- CV, coefficient of variation
- IRB, institutional review board
- LOD, logarithm of odds
- MC5R, melanocortin receptor five
- MODY, maturity-onset diabetes of the young
- NPL, nonparametric linkage
- OGTT, oral glucose tolerance test
- RFLP, restriction fragment–length polymorphism
- WHO, World Health Organization
- WHR, waist circumference to hip circumference
Footnotes
-
Address correspondence and reprint requests to Dr. Alex Parker, Millennium Pharmaceuticals Inc., 640 Memorial Dr., Cambridge, MA 02139. E-mail: aparker{at}mpi.com.
Received for publication 7 October 1999 and accepted in revised form 5 December 2000.
J.D.T. holds stock in Warner-Lambert.
Additional information can be found in an online appendix at www.diabetes.org/diabetes/appendix.asp.
