title: Functional coding variants in SLC6A15, a possible risk gene for major depression.
abstract: SLC6A15 is a neuron-specific neutral amino acid transporter that belongs to the solute carrier 6 gene family. This gene family is responsible for presynaptic re-uptake of the majority of neurotransmitters. Convergent data from human studies, animal models and pharmacological investigations suggest a possible role of SLC6A15 in major depressive disorder. In this work, we explored potential functional variants in this gene that could influence the activity of the amino acid transporter and thus downstream neuronal function and possibly the risk for stress-related psychiatric disorders. DNA from 400 depressed patients and 400 controls was screened for genetic variants using a pooled targeted re-sequencing approach. Results were verified by individual re-genotyping and validated non-synonymous coding variants were tested in an independent sample (N = 1934). Nine variants altering the amino acid sequence were then assessed for their functional effects by measuring SLC6A15 transporter activity in a cellular uptake assay. In total, we identified 405 genetic variants, including twelve non-synonymous variants. While none of the non-synonymous coding variants showed significant differences in case-control associations, two rare non-synonymous variants were associated with a significantly increased maximal (3)H proline uptake as compared to the wildtype sequence. Our data suggest that genetic variants in the SLC6A15 locus change the activity of the amino acid transporter and might thus influence its neuronal function and the risk for stress-related psychiatric disorders. As statistically significant association for rare variants might only be achieved in extremely large samples (N >70,000) functional exploration may shed light on putatively disease-relevant variants.
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany. quast@mpipsykl.mpg.de
authors.forename: Carina
authors.initials: C
authors.lastname: Quast
authors.forename: Serena
authors.initials: S
authors.lastname: Cuboni
authors.forename: Daniel
authors.initials: D
authors.lastname: Bader
authors.forename: André
authors.initials: A
authors.lastname: Altmann
authors.forename: Peter
authors.initials: P
authors.lastname: Weber
authors.forename: Janine
authors.initials: J
authors.lastname: Arloth
authors.forename: Simone
authors.initials: S
authors.lastname: Röh
authors.forename: Tanja
authors.initials: T
authors.lastname: Brückl
authors.forename: Marcus
authors.initials: M
authors.lastname: Ising
authors.forename: Anna
authors.initials: A
authors.lastname: Kopczak
authors.forename: Angelika
authors.initials: A
authors.lastname: Erhardt
authors.forename: Felix
authors.initials: F
authors.lastname: Hausch
authors.forename: Susanne
authors.initials: S
authors.lastname: Lucae
authors.forename: Elisabeth B
authors.initials: EB
authors.lastname: Binder
mesh_terms: D000328:Adult; D002460:Cell Line; D003865:Major Depressive Disorder / Q000235:genetics*; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization