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

New Orleans, Luisiana, USA

Congreso; American Society of Human Genetics (ASHG) Meeting; 2006

American Society of Human Genetics (ASHG)

Attention-Deficit/Hyperactivity Disorder (ADHD) (OMIM 143465), the most commonbehavioral disorder of childhood, affects 8-12% of children worldwide. We describedlinkage 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 sameisolate validated our linkage results and defined a minimal critical region (MCR). Acommon 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 additionalmarkers, iteratively validated the presence of the core haplotype in additional ADHDfamilial 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 haplotypeconferred protection against ADHD. The haplotype defines a single gene. Aphylogenetic reconstruction using the chimpanzee sequence for our gene as an outgrouprevealed the ADHD susceptibility haplotype ancestral to the protective variants.We also demonstrated that the gene we identified is expressed specifically in brainregions associated with ADHD. This is the first gene with variants conferring susceptibilityto 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 suggeststhat a selective advantage may be involved. The susceptibility gene will be fully characterizedat the presentation of this work.