Limitations of stratifying sib-pair data in common disease linkage studies: an example using chromosome 10p14-10q11 in type 1 diabetes.
IDDM10 on chromosome 10p11-q11 has been identified as a putative diabetes susceptibility locus through affected sib-pair (ASP) linkage analysis in UK nuclear families [Davies et al., 1994: Nature 371:130-136; Reed et al., 1997: Hum Mol Genet 6:1011-1016; Mein et al., 1998: Nat Genet 19:297-300]. We extended analysis of linkage to type 1 diabetes in this region by typing a total of 61 markers in a maximum of 418 UK sib-pairs (UK418; peak MLS = 3.84). We then stratified the dataset based on analyses performed previously by both our group [Mein et al., 1998: Nat Genet 19:297-300] and others [Paterson et al., 1999: Hum Hered 49:197-204; Paterson and Petronis, 1999a: Am J Med Genet 84:15-19; Paterson and Petronis, 2000a: J Med Genet 37:186-191; Paterson and Petronis, b: Eur J Hum Genet 8:145-148] and used a permutation procedure to assess the significance of the results. We conclude that the results obtained had a high probability of occurring by chance alone. These data highlight the limitations of stratifying small datasets (n < 500) by additional criteria and the recurrent problems of multiple testing in genetic analysis.
Johnson
Gillian C L
GC
JDRF/WT Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
Koeleman
Bobby P C
BP
Todd
John A
JA
D000367:Age Factors; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005192:Family Health; D005260:Female; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics; D006801:Humans; D008297:Male; D016555:Matched-Pair Analysis; D018895:Microsatellite Repeats; D009679:Nuclear Family; D012737:Sex Factors; D035781:Siblings
D006684:HLA-DR Antigens