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: 3.42). 12/2006; 141B(8):861-7. DOI: 10.1002/ajmg.b.30356
Source: PubMed


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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    ABSTRACT: Autism is a complex neurodevelopmental disorder characterized by impaired reciprocal social interaction, communication deficits and repetitive behaviors. A very large number of genes have been linked to autism, many of which encode proteins involved in the development and function of synaptic circuitry. However, the manner in which these mutated genes might participate, either individually or together, to cause autism is not understood. One factor known to exert extremely broad influence on brain development and network formation, and which has been linked to autism, is the neurotransmitter serotonin. Unfortunately, very little is known about how alterations in serotonin neuronal function might contribute to autism. To test the hypothesis that serotonin dysfunction can contribute to the core symptoms of autism, we analyzed mice lacking brain serotonin (via a null mutation in the gene for tryptophan hydroxylase 2 (TPH2)) for behaviors that are relevant to this disorder. Mice lacking brain serotonin (TPH2-/-) showed substantial deficits in numerous validated tests of social interaction and communication. These mice also display highly repetitive and compulsive behaviors. Newborn TPH2-/- mutant mice show delays in the expression of key developmental milestones and their diminished preference for maternal scents over the scent of an unrelated female is a forerunner of more severe socialization deficits that emerge in weanlings and persist into adulthood. Taken together, these results indicate that a hypo-serotonin condition can lead to behavioral traits that are highly characteristic of autism. Our findings should stimulate new studies that focus on determining how brain hyposerotonemia during critical neurodevelopmental periods can alter the maturation of synaptic circuits known to be mis-wired in autism and how prevention of such deficits might prevent this disorder.
    PLoS ONE 11/2012; 7(11):e48975. DOI:10.1371/journal.pone.0048975 · 3.23 Impact Factor
    • "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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    ABSTRACT: We conducted a detailed association analysis between the tryptophan hydroxylase 2 gene and autism spectrum disorders in a Japanese population using 19 markers, including tagging single nucleotide polymorphisms and a novel missense variation, p.R225Q, identified through exon resequencing. However, we failed to obtain supportive evidence for an association.
    Psychiatry Research 02/2012; 196(2-3):320-2. DOI:10.1016/j.psychres.2011.09.001 · 2.47 Impact Factor
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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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    ABSTRACT: Autism is a severe childhood disorder already presenting in the first 3 years of life and, therefore, strongly correlated with neurodevelopmental alterations in prenatal, as well as postnatal period. Neurotransmitters hold a pivotal role in development by providing the stimulation needed for synapses and neuronal networks to be formed during the critical period of neuroplasticity. Aberrations of the serotonergic system modify key processes in the developing brain and are strongly implicated in the pathophysiology of developmental disorders. Evidence for the role of serotonin in autism emerges from neuropathological, imaging and genetic studies. Due to its developmental arrest, autism requires early intervention that would, among others, target the disrupted serotonergic system and utilize brain plasticity to elicit clinically important brain changes in children.
    DNA research: an international journal for rapid publication of reports on genes and genomes 06/2009; 7(2):150-7. DOI:10.2174/157015909788848848 · 3.05 Impact Factor
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