Genome-wide linkage analysis assessing parent-of-origin effects in the inheritance of birth weight

Abstract.

Family studies suggest that genetic variation may influence birth weight. We have assessed linkage of birth weight in a genome-wide scan in 269 Pima Indian siblings (334 sibling pairs, 92 families). As imprinting (expression of only a single copy of a gene depending on parent-of-origin), is commonly found in genes that affect fetal growth, we used a recently described modification of standard multipoint variance-component methods of linkage analysis of quantitative traits. This technique allows for comparison of linkage models that incorporate imprinting effects (in which the strength of linkage is expressed as LOD_IMP) and models where parent-of-origin effects are not included (LOD_EQ). Where significant evidence of linkage was present, separate contributions of alleles derived from father (LOD_FA) or mother (LOD_MO) to the imprinting model were estimated. Significant evidence of linkage was found on chromosome 11 (at map position 88 cM, LOD_IMP=3.4) with evidence for imprinting (imprinting model superior, P<0.001). In this region, birth weight was linked predominantly to paternally derived alleles (LOD_FA=4.1, LOD_MO=0.0). An imprinted gene on chromosome 11 may influence birth weight in the Pima population. This chromosome contains one of the two major known clusters of imprinted genes in the human genome, lending biological plausibility to our findings.