A family‐based study of Indian subjects from Kolkata reveals allelic association of the serotonin transporter intron‐2 (STin2) polymorphism and attention‐deficit‐hyperactivity disorder (ADHD)

Abstract

Serotonin transporter (SLC6A4) polymorphisms are variously implicated in mediating susceptibility to attention-deficit-hyperactivity disorder (ADHD), a highly heritable and heterogeneous disorder with onset in childhood. Since there has been no survey in this regard from India, a sample of 56 ADHD cases and 174 healthy individuals from Kolkata were genotyped for the SLC6A4 promoter (5-HTTLPR) and intron-2 (STin2) polymorphisms. We report that the observed distribution of allele frequencies is consonant with that expected as per Hardy-Weinberg equilibrium proportions. Pair-wise combination of alleles comprising the 5-HTTLPR and STin2 polymorphic systems exhibit significant (chi(2) = 14.74, df = 1; P = 0.0001) linkage disequilibrium of low magnitude (D' = 0.269). The estimates of haplotype-based haplotype relative risk (HHRR) (chi(2) = 4.92, P = 0.027; RR = 1.47; 95% CI = 1.01-2.13) and transmission disequilibrium test (TDT) statistics (chi(2) = 7.00, P = 0.008; OR = 3.00; 95% CI = 1.53-5.90) using a family-based study design, indicate significant preferential transmission of the STin2.12 (A12) allele to ADHD cases. Maternal inheritance of the A12 allele is significant in terms of the HHRR (chi(2) = 6.53, P = 0.011; RR = 2.00; 95% CI = 1.08-3.72) and TDT (chi(2) = 8.07, P = 0.005; OR = 6.50; 95% CI = 1.76-23.98) suggesting a novel role for epigenetic mechanisms in the etiology of ADHD. Similar analyses yielded no evidence of association between the 5-HTTLPR polymorphism and ADHD. Studies including additional polymorphic markers, ADHD subjects and other ethnic groups are warranted to further substantiate the present findings.

Candidate gene studies of ADHD: a meta-analytic review

“…Ten TDT (Banerjee et al 2006;Heiser et al 2007;Kent et al 2002;Kim et al 2005a;Li et al 2007;Waldman et al unpublished data;Wigg et al 2006;Xu et al 2008Xu et al , 2005b and nine Case-Control/HHRR (Beitchman et al 2003;Curran et al 2005;Guimares et al 2007;Kopeckova et al 2008;Langley et al 2003;Manor et al 2001;Seeger et al 2001;Zhao et al 2005;Zoroglu et al 2002) studies were identiWed for the present meta-analysis of the association between childhood ADHD and the 5HTTLPR with the long variant designated as the "risk" allele. Results of this metaanalysis, shown in Fig.…”

“…For the meta-analysis of association between childhood ADHD and the 5HTT STin2 polymorphism, two TDT (Li et al 2007;Xu et al 2008) and seven Case-Control/HHRR (Banerjee et al 2006;Heiser et al 2007;Kim et al 2005a;Langley et al 2003;Xu et al 2005b;Zoroglu et al 2002) studies were identiWed. Based on an initial study reporting reduced prevalence of the 12-repeat allele among children diagnosed with ADHD (Zoroglu et al 2002), the 10-repeat allele of the STin2 polymorphism was designated as the "risk" allele.…”

Parent-of-origin effects of FAS and PDLIM1 in attention-deficit/hyperactivity disorder

“…These genes have been reported to have paternal or maternal transmission or parent-of-origin effects in ADHD in previous studies. [6][7][8][9][10][11][12][13][14][15] In the cleaned SNP data, we did not find any SNPs in the DRD4 gene. Furthermore, we could not confirm the paternal or maternal transmission or parent-oforigin effects (p < 0.01) for HTR1B, SLC6A4, DRD4, DRD5 and FADS2.…”

No association between two polymorphisms of the serotonin transporter gene and combined type attention deficit hyperactivity disorder

“…In accord with these data two other studies found that short/short genotype was significantly underrepresented in children with ADHD compared to controls [Manor et al, 2001;Zorog lu et al, 2002]. However, Li et al [2007] reported a preferential transmission of the short-allele to ADHD offspring in a Chinese sample and six further studies did not find any association between the polymorphism and ADHD [Langley et al, 2003;Kim et al, 2005;Xu et al, 2005;Banerjee et al, 2006;Wigg et al, 2006;Heiser et al, 2007]. A study that combined the available data by pooling odds ratios across studies found a small but significant association of the long allele of 5-HTTLPR with ADHD [Faraone et al, 2005].…”

“…For the STin2-VNTR marker one study found that the 12/12 genotype was significantly less frequent in ADHD cases compared to controls [Zorog lu et al, 2002], while another study found that the 12-repeat allele was preferentially overtransmitted to ADHD offspring [Banerjee et al, 2006]. A further seven studies did not demonstrate an association between STin2-VNTR and ADHD [Kent et al, 2002;Langley et al, 2003;Curran et al, 2005;Kim et al, 2005;Xu et al, 2005;Heiser et al, 2007;Li et al, 2007].…”