A second-generation screen of the human genome for susceptibility to insulin-dependent diabetes mellitus

Abstract

During the past decade, the genetics of type 1 (insulin-dependent) diabetes mellitus (IDDM) has been studied extensively and the disorder has become a paradigm for genetically complex diseases. Previous genome screens1,2 and studies focused on candidate genes3,4,5,6,7,8,9 have provided evidence for genetic linkage between polymorphic DNA markers and 15 putative IDDM susceptibility loci, designated IDDM1-IDDM15 . We have carried out a second-generation screen of the genome for linkage and analysed the data by multipoint linkage methods. An initial panel of 212 affected sibpairs (ASPs) was genotyped for 438 markers spanning all autosomes, and an additional 467 ASPs were used for follow-up genotyping. Other than the well-established linkage with the HLA region at chromosome 6p21.3, there was only one region, located on chromosome 1q and not previously reported, where the log likelihood ratio (lod) was greater than 3. Lods between 1.0 and 1.8 were found in six other regions, three of which have been reported in other studies. Another reported region10, on chromosome 6q and loosely linked to HLA, also had an elevated lod. Little or no support was found for most reported IDDM loci (lods were less than 1), despite larger sample sizes in the present study.

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Figure 1: Multipoint lod map of IDDM and markers on chromosome 1.
Figure 2: Multipoint lod map of IDDM and markers on chromosomes 2, 6, 8 and 10; each has at least one site with lod greater than 1.
Figure 3: Multipoint lod map of IDDM and markers on 17 chromosomes where there was no region with lod greater than 1.

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Acknowledgements

We are grateful for advice and assistance from R. McGinnis, M. Urbanek and L. Pinchuk, and for technical assistance by C. Blume, P. Byers, I. Edenburg, J. Ladik, J. Salvin, P. Wexler and Y. Yang. We thank the Human Biological Data Interchange and the British Diabetic Association for providing DNA samples and information about the families. This work was supported by linked NIH grants DK 46635 (P.C.), DK46627 (G.I.B.) and DK46618 (R.S.S.).

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Correspondence to Patrick Concannon or Richard S. Spielman.

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Concannon, P., Gogolin-Ewens, K., Hinds, D. et al. A second-generation screen of the human genome for susceptibility to insulin-dependent diabetes mellitus. Nat Genet 19, 292–296 (1998). https://doi.org/10.1038/985

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