A common ancestral haplotype located at 4q13.2 confers susceptibility to ADHD.

ARCOS-BURGOS MAURICIO; JAIN M; DOMENE S; SHIVELY S; WALLIS D; STANESCU H; KARKERA JD; ACOSTA MT; BERG K; KLETA R; ROESSLER E; VORTMEYER A; PINEDA D; PALACIO JD; LOPERA F; MEYER J; LESCH KP; BAILEY-WILSON JE; CASTELLANOS FX; MUENKE M

Gettysburg, Pensylvannia, USA

Jornada; National Human Genome Research Institute (NHGRI) Scientific Retreat; 2006

National Human Genome Research Institute (NHGRI)

Attention-Deficit/Hyperactivity Disorder (ADHD) (OMIM 143465), the most common behavioral disorder of childhood, affects 8-12% of children worldwide. We described linkage of ADHD to a locus at 4q13.2 in families from a genetic isolate in Colombia, South America. Fine mapping and a second set of families (n=120) from this same isolate validated our linkage results and defined a minimal critical region (MCR). A common haplotype (frequency, 22.2%) within this MCR was found in LD to ADHD (P < 2.7*10-5). ADHD susceptibility haplotype variants reconstructed from 23 additional markers, iteratively validated the presence of the core haplotype in additional ADHD familial samples from the US(n=185, P<3.1*10-3) and from Germany (n=244, P<3.8*10- 5) (Ppooled< 3.01*10-8) (RR 2.6). Variants complementary to the susceptibility haplotype conferred protection against ADHD. The haplotype defines a single gene. A phylogenetic reconstruction using the chimpanzee sequence for our gene as an outgroup revealed the ADHD susceptibility haplotype ancestral to the protective variants. We also demonstrated that the gene we identified is expressed specifically in brain regions associated with ADHD. This is the first gene with variants conferring susceptibility to ADHD with an effect size (genotype relative risk) greater than 2.0. In addition, the evolutionary history and the high frequency of the susceptibility haplotype suggests that a selective advantage may be involved. The susceptibility gene will be fully characterized at the presentation of this work.