Smoller Jordan W, Biederman Joseph, Arbeitman Lori, Doyle Alysa E, Fagerness Jes, Perlis Roy H, Sklar Pamela, Faraone Stephen V
Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Biol Psychiatry. 2006 Mar 1;59(5):460-7. doi: 10.1016/j.biopsych.2005.07.017. Epub 2005 Sep 28.
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.
临床前和遗传学研究表明5-羟色胺1B受体基因（HTR1B）与注意力缺陷多动障碍（ADHD）有关。已观察到该基因与一个单核苷酸多态性（SNP；G861C）存在关联，但尚未见更广泛的连锁不平衡分析报道。
为研究单倍型结构，我们对12个多代CEPH家系中该基因及其周围的21个SNP进行了基因分型。我们确定了一个包含HTR1B的单倍型块，并对229个ADHD先证者家系中该块内或其侧翼的8个SNP进行了单倍型和单标记关联分析。鉴于先前的研究表明ADHD不同亚型存在不同的遗传影响，我们还研究了与注意力不集中型和混合型亚型的关联。
我们观察到G861等位基因向ADHD后代的传递无显著过度现象（单尾p = 0.07）。对包含HTR1B的单倍型块进行的单标记和单倍型检验未发现与ADHD的其他关联。然而，该单倍型块与注意力不集中型亚型相关（总体p < 0.01）。此外，该块内的三个SNP与注意力不集中型亚型名义上相关（p < 0.05），尽管在多重检验校正后这些相关性不再显著。如先前研究报道，我们发现G等位基因向ADHD后代的父系过度传递；这似乎主要归因于注意力不集中型病例。
这些分析表明HTR1B基因的变异可能主要影响ADHD的注意力不集中型亚型。
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