Attention deficit hyperactivity disorder: fine mapping supports linkage to 5p13, 6q12, 16p13, and 17p11

Abstract

We completed fine mapping of nine positional candidate regions for attention-deficit/hyperactivity disorder (ADHD) in an extended population sample of 308 affected sibling pairs (ASPs), constituting the largest linkage sample of families with ADHD published to date. The candidate chromosomal regions were selected from all three published genomewide scans for ADHD, and fine mapping was done to comprehensively validate these positional candidate regions in our sample. Multipoint maximum LOD score (MLS) analysis yielded significant evidence of linkage on 6q12 (MLS 3.30; empiric P=.024) and 17p11 (MLS 3.63; empiric P=.015), as well as suggestive evidence on 5p13 (MLS 2.55; empiric P=.091). In conjunction with the previously reported significant linkage on the basis of fine mapping 16p13 in the same sample as this report, the analyses presented here indicate that four chromosomal regions--5p13, 6q12, 16p13, and 17p11--are likely to harbor susceptibility genes for ADHD. The refinement of linkage within each of these regions lays the foundation for subsequent investigations using association methods to detect risk genes of moderate effect size.

Figure 1

Multipoint MLS values for nine candidate regions in 308 ASPs with ADHD. The X-axis values are distances from the p-telomere, in Kosambi cM. The MLS values for the 10-cM genomewide scan of 270 ASPs (Ogdie et al. 2003) are shown in red. The fine-mapping values, at ∼ 2-cM marker density in candidate regions, are shown in blue. The blue bar indicates the approximate fine-mapping interval. The identical MLS values for the 2-cM and 10-cM analyses for chromosomes 7 and 9 and a large portion of chromosome 15 give the appearance of a single line. MLS analysis was performed by ASPEX sib_ibd, under the possible triangle.