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Association Between the 5HT1B Receptor Gene (HTR1B) and the Inattentive Subtype of ADHD

2005; Elsevier BV; Volume: 59; Issue: 5 Linguagem: Inglês

10.1016/j.biopsych.2005.07.017

1873-2402

Jordan W. Smoller, Joseph Biederman, Lori Arbeitman, Alysa E. Doyle, Jes Fagerness, Roy H. Perlis, Pamela Sklar, Stephen V. Faraone,

Genetics and Neurodevelopmental Disorders

Background Preclinical and genetic studies have implicated the 5HT1B receptor gene (HTR1B) in attention-deficit/hyperactivity disorder (ADHD). Association with a single nucleotide polymorphism (SNP; G861C) has been observed, but more extensive linkage disequilibrium analyses have not been reported. Methods To examine haplotype structure, we genotyped 21 SNPs in and around the gene in 12 multigenerational CEPH pedigrees. We identified a haplotype block encompassing HTR1B and performed haplotype and single-marker association analyses for the eight SNPs within or flanking this block in 229 families of ADHD probands. In light of previous studies suggesting distinct genetic influences on ADHD subtypes, we also examined association with the inattentive and combined subtypes. Results We observed nonsignificant overtransmission of the G861 allele to ADHD offspring (one-tailed p = .07). Single-marker and haplotype tests of a haplotype block encompassing HTR1B revealed no other associations with ADHD. However, this haplotype block was associated with the inattentive subtype (global p < .01). Additionally, three SNPs in this block were nominally (p < .05) associated with the inattentive subtype, although these did not remain significant after correction for multiple testing. As reported in previous studies, we found paternal overtransmission of the G861 allele to offspring with ADHD; this appeared to be largely attributable to inattentive cases. Conclusions These analyses suggest that variation in the HTR1B gene may primarily affect the inattentive subtype of ADHD. Preclinical and genetic studies have implicated the 5HT1B receptor gene (HTR1B) in attention-deficit/hyperactivity disorder (ADHD). Association with a single nucleotide polymorphism (SNP; G861C) has been observed, but more extensive linkage disequilibrium analyses have not been reported. To examine haplotype structure, we genotyped 21 SNPs in and around the gene in 12 multigenerational CEPH pedigrees. We identified a haplotype block encompassing HTR1B and performed haplotype and single-marker association analyses for the eight SNPs within or flanking this block in 229 families of ADHD probands. In light of previous studies suggesting distinct genetic influences on ADHD subtypes, we also examined association with the inattentive and combined subtypes. We observed nonsignificant overtransmission of the G861 allele to ADHD offspring (one-tailed p = .07). Single-marker and haplotype tests of a haplotype block encompassing HTR1B revealed no other associations with ADHD. However, this haplotype block was associated with the inattentive subtype (global p < .01). Additionally, three SNPs in this block were nominally (p < .05) associated with the inattentive subtype, although these did not remain significant after correction for multiple testing. As reported in previous studies, we found paternal overtransmission of the G861 allele to offspring with ADHD; this appeared to be largely attributable to inattentive cases. These analyses suggest that variation in the HTR1B gene may primarily affect the inattentive subtype of ADHD.