Abstract
Genetic association studies of SLC6A4 (SERT) and obsessive-compulsive disorder (OCD) have been equivocal. We genotyped 1241 individuals in 278 pedigrees from the OCD Collaborative Genetics Study for 13 single-nucleotide polymorphisms, for the linked polymorphic region (LPR) indel with molecular haplotypes at rs25531, for VNTR polymorphisms in introns 2 and 7 and for a 381-bp deletion 3′ to the LPR. We analyzed using the Family-Based Association Test (FBAT) under additive, dominant, recessive and genotypic models, using both OCD and sex-stratified OCD as phenotypes. Two-point FBAT analysis detected association between Int2 (P=0.0089) and Int7 (P=0.0187) (genotypic model). Sex-stratified two-point analysis showed strong association in females with Int2 (P<0.0002), significant after correction for linkage disequilibrium, and multiple marker and model testing (PAdj=0.0069). The SLC6A4 gene is composed of two haplotype blocks (our data and the HapMap); FBAT whole-marker analysis conducted using this structure was not significant. Several noteworthy nonsignificant results have emerged. Unlike Hu et al., we found no evidence for overtransmission of the LPR LA allele (genotype relative risk=1.11, 95% confidence interval: 0.77–1.60); however, rare individual haplotypes containing LA with P<0.05 were observed. Similarly, three individuals (two with OCD/OCPD) carried the rare I425V SLC6A4 variant, but none of them passed it on to their six OCD-affected offspring, suggesting that it is unlikely to be solely responsible for the ‘OCD plus syndrome’, as reported by Ozaki et al. In conclusion, we found evidence of genetic association at the SLC6A4 locus with OCD. A noteworthy lack of association at the LPR, LPR-rs25531 and rare 425V variants suggests that hypotheses about OCD risk need revision to accommodate these new findings, including a possible gender effect.
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Acknowledgements
We thank the many families who have participated in the OCGS; the OCF; Ann Pulver, PhD, Kathleen Merikangas, PhD, David Houseman, MD and Alec Wilson, PhD, for consultation; and clinicians and coordinators at each OCGS site: Providence (Maria Mancebo, PhD, Richard Marsland, RN and Shirley Yen, PhD); New York (Renee Goodwin, PhD, Joshua Lipsitz, PhD and Jessica Page, PsyD); Baltimore (Laura Eisen, BS, Karan Lamb, PsyD, Tracey Lichner, PhD, Yung-mei Leong, PhD and Krista Vermillion, BA); Boston (Dan Geller, MD, Anne Chosak, PhD, Michelle Wedig, BS, Evelyn Stewart, MD, Michael Jenike, MD, Beth Gershuny, PhD and Sabine Wilhelm, PhD); Bethesda (Lucy Jestement, Diane Kazuba, V Holland LaSalle-Ricci and Theresa B DeGuzman); and Los Angeles (R Lindsey Bergman, PhD, Susanna Chang, PhD, Audra Langley, PhD and Amanda Pearlman, BA). In addition, we wish to thank Jason Briggs at ABI for his technical assistance during set-up of the SNPlex assay in a high-throughput, 384-well robotized format, Ming-Chen Chien, MS, at the Columbia University Genome Center, Dave Conti, USC, Keck School, Biostatistics and Dr Jonathan Liu and colleagues, Soft Genetics, Inc. for early design versions of Gene Marker & Mutation Surveyor softwares.
Funding Source: This study is supported by NIMH R01 MH50214 and NIH/NCRR/OPD-GCRC RR00052 (GN). EV is a recipient of a 2006 grant award from the Obsessive Compulsive Foundation (OCF) and a departmental fellowship award (USC, Keck School, Psychiatry). OE received a Young Investigator Award from NARSAD. YYS initiated her contribution to this report while working at JHU, and is currently working at the Genomic Research Branch, NIMH. Part of this work was completed as her outside activity, and as such the views expressed in this article do not necessarily represent the views of the NIMH, NIH, HHS, or the US Government. SAR and DLP are funded by the NIMH. SLR has received honoraria and/or consultation fees from Neurogen, Sepracor, Novartis and Medtronic, and has conducted research funded by Medtronic, Cyberonics, Cephalon and Northstar. JTM has received research support from Eli Lilly, Bristol Myers, Squibb, Seaside Pharmaceuticals, and Aspect. Other relevant NIMH awards: K23-MH066284 (MG) & K23-MH64543 (OJB). JAK is funded by the NIMH, CMREF and NARSAD, and this project was funded by NIMH grants MH079494 & MH050214. He is a member of the scientific advisory boards of SoftGenetics, Inc. & Life Technologies, Inc. and has received compensation from the latter.
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Voyiaziakis, E., Evgrafov, O., Li, D. et al. Association of SLC6A4 variants with obsessive-compulsive disorder in a large multicenter US family study. Mol Psychiatry 16, 108–120 (2011). https://doi.org/10.1038/mp.2009.100
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DOI: https://doi.org/10.1038/mp.2009.100
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