An association analysis of murine anxiety genes in humans implicates novel candidate genes for anxiety disorders.
BACKGROUND
Human anxiety disorders are complex diseases with largely unknown etiology. We have taken a cross-species approach to identify genes that regulate anxiety-like behavior with inbred mouse strains that differ in their innate anxiety levels as a model. We previously identified 17 genes with expression levels that correlate with anxiety behavior across the studied strains. In the present study, we tested their 13 known human homologues as candidate genes for human anxiety disorders with a genetic association study.


METHODS
We describe an anxiety disorder study sample derived from a Finnish population-based cohort and consisting of 321 patients and 653 carefully matched control subjects, all interviewed to obtain DSM-IV diagnoses. We genotyped altogether 208 single nucleotide polymorphisms (SNPs) (all non-synonymous SNPs, SNPs that alter potential microRNA binding sites, and gap-filling SNPs selected on the basis of HapMap information) from the investigated anxiety candidate genes.


RESULTS
Specific alleles and haplotypes of six of the examined genes revealed some evidence for association (p < or = .01). The most significant evidence for association with different anxiety disorder subtypes were: p = .0009 with ALAD (delta-aminolevulinate dehydratase) in social phobia, p = .009 with DYNLL2 (dynein light chain 2) in generalized anxiety disorder, and p = .004 with PSAP (prosaposin) in panic disorder.


CONCLUSIONS
Our findings suggest that variants in these genes might predispose to specific human anxiety disorders. These results illustrate the potential utility of cross-species approaches in identification of candidate genes for psychiatric disorders.
Donner
Jonas
J
Research Program of Molecular Neurology, Biomedicum Helsinki, Finland; Department of Medical Genetics, University of Helsinki, Helsinki, Finland; Department of Molecular Medicine, National Public Health Institute and FIMM, Institute of Molecular Medicine Finland, Helsinki, Finland.
Pirkola
Sami
S
Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland; Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland.
Silander
Kaisa
K
Department of Molecular Medicine, National Public Health Institute and FIMM, Institute of Molecular Medicine Finland, Helsinki, Finland.
Kananen
Laura
L
Research Program of Molecular Neurology, Biomedicum Helsinki, Finland; Department of Medical Genetics, University of Helsinki, Helsinki, Finland; Department of Molecular Medicine, National Public Health Institute and FIMM, Institute of Molecular Medicine Finland, Helsinki, Finland.
Terwilliger
Joseph D
JD
Faculty of Medicine, University of Helsinki, Helsinki, Finland; Department of Genetics and Development, Department of Psychiatry, Columbia Genome Center, Columbia University, New York, New York; Division of Medical Genetics, New York State Psychiatric Institute, New York, New York.
Lönnqvist
Jouko
J
Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland; Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland.
Peltonen
Leena
L
Department of Medical Genetics, University of Helsinki, Helsinki, Finland; Department of Molecular Medicine, National Public Health Institute and FIMM, Institute of Molecular Medicine Finland, Helsinki, Finland; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
Hovatta
Iiris
I
Research Program of Molecular Neurology, Biomedicum Helsinki, Finland; Department of Medical Genetics, University of Helsinki, Helsinki, Finland; Department of Molecular Medicine, National Public Health Institute and FIMM, Institute of Molecular Medicine Finland, Helsinki, Finland; Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland. Electronic address: iiris.hovatta@helsinki.fi.
D000818:Animals; D001008:Anxiety Disorders / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D016555:Matched-Pair Analysis; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
D009419:Nerve Tissue Proteins