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Functional studies and rare variant screening of SLC1A1/EAAC1 in males with obsessive–compulsive disorder

Veenstra-VanderWeele, Jeremya,b,c,d,e; Xu, Tima; Ruggiero, Alicia M.b; Anderson, Lauren R.a; Jones, Shaine T.a; Himle, Joseph A.f; Kennedy, James L.g; Richter, Margaret A.h; Hanna, Gregory L.f; Arnold, Paul D.g,i,j

doi: 10.1097/YPG.0b013e328353fb63
Brief Reports

Several studies have found that the neuronal glutamate transporter gene SLC1A1/EAAC1 is associated with obsessive–compulsive disorder (OCD), with a stronger association in males. Previous studies have primarily focused on common single-nucleotide polymorphisms, rather than rare functional variants that are likely to have larger effects. We screened 184 males with OCD for rare variation in SLC1A1 exons; however, no new coding variation was found. When combined with previous screens, only one SLC1A1 amino acid variant has been detected among the 841 individuals screened, which is less than for other neurotransmitter transporter genes (P=0.0001). We characterized the function of the one SLC1A1 missense variant reported previously in OCD, Thr164Ala, and found that the Ala164 allele leads to decreased Vmax and Km (P<0.0001) in transfected human embryonic kidney cells. Further work will be necessary to understand the impact of this rare SLC1A1/EAAC1 Ala164 variant on neuronal function and circuitry relevant to OCD.

Departments of aPsychiatry

bPharmacology

cPediatrics

dCenter for Molecular Neuroscience

eKennedy Center for Research on Human Development, University of Vanderbilt, Nashville, Tennessee

fDepartment of Psychiatry, University of Michigan, Ann Arbor, Michigan, USA

gNeurogenetics Section, Centre for Addiction and Mental Health

hDepartment of Psychiatry, Sunnybrook Health Sciences Centre, University of Toronto

iProgram in Genetics and Genomic Biology

jDepartment of Psychiatry, Hospital for Sick Children, Toronto, Ontario, Canada

Margaret A. Richter, Gregory L. Hanna, and Paul D. Arnold have contributed equally to the writing of this article.

Correspondence to Jeremy Veenstra-VanderWeele, MD, 465 21st Ave S, 7158 MRB III, Nashville, TN 37232, USA Tel: +1 615 936 1701; fax: +1 615 936 7475; e-mail: j.vvw@vanderbilt.edu

Received May 20, 2011

Accepted January 15, 2012

© 2012 Lippincott Williams & Wilkins, Inc.