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A Genome-Wide Scan in Type 2 Diabetes Mellitus Provides Independent Replication of a Susceptibility Locus on 18p11 and Suggests the Existence of Novel Loci on 2q12 and 19q13

Departments of Medical Genetics (J.H.O.v.T., L.A.S., E.S., H.v.S., C.A.E.R.-A., P.L.P., C.W.) and Internal Medicine (T.W.v.H.), University Medical Center, 3583 EA Utrecht, The Netherlands

Address all correspondence and requests for reprints to: Cisca Wijmenga, Ph.D., Department of Medical Genetics, KC04.084.2, University Medical Center Utrecht, Wilhelmina Kinder Ziekenhuis, Lundlaan 6, 3584 EA Utrecht, The Netherlands. E-mail: t.n.wijmenga{at}med.uu.nl.

A genome-wide scan was performed, using nonparametric linkage analyses, to find susceptibility loci for type 2 diabetes mellitus in the Dutch population. We studied 178 families from The Netherlands, who constituted 312 affected sibling pairs. The first stage of the genome scan consisted of 270 DNA markers, with an average intermarker spacing of 13 cM. Because obesity and type 2 diabetes mellitus are interrelated, the data set was stratified for the subphenotype body mass index, corrected for age and gender. This resulted in a suggestive maximum multipoint LOD score of 2.3 (single-point P value, 9.7 x 10^-4; genome-wide P value, 0.028) for the most obese 20% pedigrees of the data set, between marker loci D18S471 and D18S843. In the lowest 80% obese pedigrees, two interesting loci on chromosome 2 and 19 were found, with LOD scores of 1.5 and 1.3. We provide independent evidence that the chromosome 18p11 locus, reported earlier from a Finnish/Swedish population, is of definite interest for type 2 diabetes mellitus in connection with obesity. Subsequently, our results indicate that two novel loci may reside on chromosomes 2 and 19, with minor effects involved in the development of type 2 diabetes mellitus in the Dutch population.

This work was financially supported by the Dutch Diabetes Research Foundation (Diabetes Fonds Nederland Grant 97.114, to C.W. and T.W.v.H.).

¹ This paper is dedicated to the memory of Lodewijk Sandkuijl (1953–2002). He was a world expert on biostatistics and an inspiration to us.

Abbreviation: BMI, Body mass index; DS, diabetes subjects.

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