{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTTC12 is emerging as a key gene within a cluster that influences addictive behaviors. Several studies have demonstrated that genetic variants in TTC12, especially those mapping to exon 3, are robustly associated with nicotine, alcohol, and opioid dependence as well as smoking behaviors in diverse populations. These associations suggest that TTC12 contributes to the risk for substance dependence through mechanisms that may involve dopaminergic transmission and interactions with the Wnt pathway—implicating effects on dopamine cell development and reward system sensitivity. Such findings help resolve earlier discrepant results concerning genes in the NCAM1‐TTC12‐ANKK1‐DRD2 cluster, supporting a pleiotropic influence on addiction liability."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its involvement in addiction, TTC12 plays a crucial role in the assembly of motile organelles. Studies of patients with primary ciliary dyskinesia (PCD) have revealed that loss-of-function mutations in TTC12 lead to defects in dynein arm assembly—in particular, the absence of outer and inner dynein arms in sperm flagella, with more selective inner dynein arm abnormalities in respiratory cilia. These findings, along with functional investigations in model organisms and tissue culture, underscore the importance of TTC12 (and related tetratricopeptide repeat family members) in the proper organization and function of cilia and flagella."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurther extending its influence beyond addiction and ciliogenesis, TTC12 variants have also been implicated in cognitive aging. Large-scale population studies have identified TTC12—as part of the dopamine receptor-related loci—as a novel candidate gene influencing cognitive function in older individuals. In this context, genetic variation in TTC12 appears to interact with lifestyle factors such as physical activity to modulate cognitive aging trajectories, suggesting that TTC12 may contribute to complex neurocognitive processes throughout the lifespan."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Joel Gelernter, Yi Yu, Roger Weiss, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Haplotype spanning TTC12 and ANKK1, flanked by the DRD2 and NCAM1 loci, is strongly associated to nicotine dependence in two distinct American populations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddl426"}], "href": "https://doi.org/10.1093/hmg/ddl426"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17085484"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17085484"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Bao-Zhu Yang, Henry R Kranzler, Hongyu Zhao, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Haplotypic variants in DRD2, ANKK1, TTC12, and NCAM1 are associated with comorbid alcohol and drug dependence."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Alcohol Clin Exp Res (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1530-0277.2008.00800.x"}], "href": "https://doi.org/10.1111/j.1530-0277.2008.00800.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18828801"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18828801"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Francesca Ducci, Marika Kaakinen, Anneli Pouta, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TTC12-ANKK1-DRD2 and CHRNA5-CHRNA3-CHRNB4 influence different pathways leading to smoking behavior from adolescence to mid-adulthood."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biol Psychiatry (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.biopsych.2010.09.055"}], "href": "https://doi.org/10.1016/j.biopsych.2010.09.055"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21168125"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21168125"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Elliot C Nelson, Michael T Lynskey, Andrew C Heath, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ANKK1, TTC12, and NCAM1 polymorphisms and heroin dependence: importance of considering drug exposure."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "JAMA Psychiatry (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1001/jamapsychiatry.2013.282"}], "href": "https://doi.org/10.1001/jamapsychiatry.2013.282"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23303482"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23303482"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Sean P David, Briana Mezuk, Peter P Zandi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sex differences in TTC12/ANKK1 haplotype associations with daily tobacco smoking in Black and White Americans."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nicotine Tob Res (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/ntr/ntp201"}], "href": "https://doi.org/10.1093/ntr/ntp201"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20133381"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20133381"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Christine Macare, Francesca Ducci, Yuning Zhang, et al. 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