STRATEGY FOR MANNING MINOR HISTOCOMPATIBILITY GENES INVOLVED IN GRAFT-VERSUS-HOST DISEASE - A NOVEL APPLICATION OF DISCORDANT SIB PAIR METHODOLOGY

We introduce a novel application for linkage analysis: using bone marr ow donor-recipient sib pairs to search for genes influential in graft- versus-host disease (GVHD), a major cause of morbidity and mortality f ollowing allogeneic bone marrow transplantation. In particular, we sho w that transplant sib pairs in which the recipient developed severe GV HD can be used to map genes in the same way as traditional discordant (affected/unaffected) sib pairs (DSPs). For a plausible GVHD model, we demonstrate that the transplant/discordant sib pair analog of the ''p ossible triangle test'' [Holmans (1993) Am J Hum Genet 52:362-374] has similar power to that of the simpler ''restricted test'' proposed by Risch [(1990b) Am J Hum Genet 46:229-241; (1992) Am J Hum Genet 51:673 -675]. Moreover, we show that the restricted test has superior power i n much of the DSP possible triangle and significantly inferior power i n only a small region. Thus, we conclude that the restricted test is p referable for localizing genes with transplant/discordant sib pairs. F inally, we examine the effects of heterogeneity on the power to detect GVHD loci and demonstrate the gain in efficiency by dividing the samp le into genetically more homogeneous subgroups. (C) 1998 Wiley-Liss, I nc.