Article

Family-based association study of TPH1 and TPH2 polymorphisms in autism

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, Borough of Manhattan, New York, United States
American Journal of Medical Genetics Part B Neuropsychiatric Genetics (Impact Factor: 3.27). 12/2006; 141B(8):861-7. DOI: 10.1002/ajmg.b.30356
Source: PubMed

ABSTRACT The TPH1 and TPH2 genes encode the rate-limiting enzymes that control serotonin biosynthesis, and serotonin is clearly altered in autism. In the current study, eight SNPs in the TPH1 gene region and eight SNPs within the TPH2 gene were examined by family-based association tests in a large cohort of 352 families with autism and in clinically defined subsets of these families with either severe obsessive-compulsive behaviors (sOCB) or self-stimulatory behaviors (SSB). We found no evidence for association between autism and single SNPs or haplotypes of the TPH1 and TPH2 genes in the cohort of all families or in the sOCB and SSB subsets. In particular, we failed to replicate the association between autism and variants of the TPH2 gene, rs4341581 (TRANSMIT P = 1; PDT P = 0.323; FBAT P = 0.446) and rs11179000 (TRANSMIT P = 0.174; PDT P = 0.293; FBAT P = 0.374). Furthermore, no evidence for linkage was observed between autism and SNPs in the TPH1 and TPH2 genes (although linkage at the TPH2 locus was observed in the SSB subset). Thus, it appears unlikely that the TPH1 and TPH2 genes play a significant role in the susceptibility to autism or to autism endophenotypes including sOCB and SSB.

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    • "A large number of psychiatric illnesses have been associated with polymorphisms in the TPH2 gene to include depression, anxiety and obsessive-compulsive disorder [106]. Studies of an association of TPH2 genetic variants with ASDs are suggesting that TPH2 may not be an ASD susceptibility gene [18], [19], [20], [21]. However, changes in the function of its protein product can have broad effects on 5HT synthesis. "
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    • "Coon et al. (2005) found associations between ASD and two out of 18 SNPs in 88 patients and 95 controls. However, subsequent family-based studies did not show an association between TPH2 and ASD in 352 families using eight SNPs (Ramoz et al., 2006) as well as in 234 families using two SNPs (Sacco et al., 2007). These conflicting findings may be due to the relatively small sample sizes and the limited number of markers used in individual studies. "
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    • "Tryptophan hydroxylase-2 (TPH2) is the rate limiting enzyme for CNS serotonin synthesis and is encoded by TPH2, whereas TPH1 encodes the peripheral isoform of the enzyme. Only one report has provided preliminary evidence for the involvement of TPH2 variants in autism [29], whereas following research has failed to confirm the association for either TPH1 or TPH2 [81,83]. Nevertheless, both genes have been shown to hold critical roles in the homeostasis of peripheral and brain serotonin respectively [8,32,51]. "
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