Background
Anxiety disorders are common psychiatric conditions that are highly comorbid with
each other and related phenotypes such as depression, likely due to a shared genetic
basis. Fear-related behaviors in mice have long been investigated as potential models
of anxiety disorders, making integration of information from both murine and human
genetic data a powerful strategy for identifying potential susceptibility genes for
these conditions.
Methods
We combined genome-wide association analysis of fear-related behaviors with strain
distribution pattern analysis in heterogeneous stock mice to identify a preliminary
list of 52 novel candidate genes. We ranked these according to three complementary
sources of prior anxiety-related genetic data: 1) extant linkage and knockout studies
in mice, 2) a meta-analysis of human linkage scans, and 3) a preliminary human genome-wide
association study. We genotyped tagging single nucleotide polymorphisms covering the
nine top-ranked regions in a two-stage association study of 1316 subjects from the
Virginia Adult Twin Study of Psychiatric and Substance Use Disorders chosen for high
or low genetic loading for anxiety-spectrum phenotypes (anxiety disorders, neuroticism,
and major depression).
Results
Multiple single nucleotide polymorphisms in the PPARGC1A gene demonstrated association in both stages that survived gene-wise correction for
multiple testing.
Conclusions
Integration of genetic data across human and murine studies suggests PPARGC1A as a potential susceptibility gene for anxiety-related disorders.
Key Words
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References
- Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication.Arch Gen Psychiatry. 2005; 62: 593-602
- A review and meta-analysis of the genetic epidemiology of anxiety disorders.Am J Psychiatry. 2001; 158: 1568-1578
- Evidence for a general neurotic syndrome.Br J Psychiatry. 1990; 157: 6-12
- Normal personality traits and comorbidity among phobic, panic and major depressive disorders.Psychiatry Res. 2001; 102: 73-85
- Personality and comorbidity of common psychiatric disorders.Br J Psychiatry. 2005; 186: 190-196
- Genetic covariation between neuroticism and the symptoms of anxiety and depression.Genet Epidemiol. 1984; 1: 89-107
- A population-based twin study of the relationship between neuroticism and internalizing disorders.Am J Psychiatry. 2006; 163: 857-864
- The sources of co-morbidity between major depression and generalized anxiety disorder in a Swedish national twin sample.Psychol Med. 2007; 37: 453-462
- Who's afraid of anxiety genetics?.Biol Psychiatry. 2011; 69: 506-507
- Advances in molecular genetics of panic disorder.Mol Psychiatry. 2010; 15: 681-701
- Genome-wide association study of panic disorder in the Japanese population.J Hum Genet. 2009; 54: 122-126
- TMEM132D, a new candidate for anxiety phenotypes: Evidence from human and mouse studies.Mol Psychiatry. 2010; 16: 647-663
- Animal models of anxiety and their molecular dissection.Semin Cell Dev Biol. 2003; 14: 37-42
- Targeted genome screen of panic disorder and anxiety disorder proneness using homology to murine QTL regions.Am J Med Genet. 2001; 105: 195-206
- An association analysis of murine anxiety genes in humans implicates novel candidate genes for anxiety disorders.Biol Psychiatry. 2008; 64: 672-680
- Genome-wide genetic association of complex traits in heterogeneous stock mice.Nat Genet. 2006; 38: 879-887
- A method for fine mapping quantitative trait loci in outbred animal stocks.Proc Natl Acad Sci U S A. 2000; 97: 12649-12654
- The Internet-based MGS2 control sample: Self report of mental illness.Am J Psychiatry. 2010; 167: 854-865
- The World Health Organization Composite International Diagnostic Interview Short Form (CIDI-SF).Int J Methods Psychiatr Res. 1998; 7: 171-185
- A revised version of the psychoticism scale.Pers Individ Dif. 1985; 6: 21-29
- Mplus User's Guide.Fourth Edition. Muthen and Muthen, Los Angeles2006
- The structure of common mental disorders.Arch Gen Psychiatry. 1999; 56: 921-926
- Genomewide association analysis followed by a replication study implicates a novel candidate gene for neuroticism.Arch Gen Psychiatry. 2008; 65: 1062-1071
- PLINK: A tool set for whole-genome association and population-based linkage analyses.Am J Med Genet. 2007; 81: 559-575
- Estimating the number and size of the main effects in genome-wide case-control association studies.BMC Proc. 2007; 1: S143
- A population-based twin study of lifetime major depression in men and women.Arch Gen Psychiatry. 1999; 56: 39-44
- Genes, Environment, and Psychopathology: Understanding the Causes of Psychiatric and Substance Use Disorders.Guilford Press, New York2006
- Structured Clinical Interview for DSM-III-R (SCID).Biometrics Research Department, New York State Psychiatric Institute, New York1985
- Manual of the Eysenck Personality Questionnaire.Hodder and Stoughton, London1975
- Catechol-O-methyltransferase contributes to genetic susceptibility shared among anxiety spectrum phenotypes.Biol Psychiatry. 2008; 64: 302-310
- The co-morbidity of anxiety and depression in the perspective of genetic epidemiology.Psychol Med. 2005; 35: 611-624
- Genetic covariation between neuroticism and the symptoms of anxiety and depression.Genet Epidemiol. 1984; 1: 89-107
- Evidence for genetic influences common and specific to symptoms of generalized anxiety and panic.J Affect Disord. 2000; 57: 25-35
- Power of selective genotyping in genetic association analyses of quantitative traits.Behav Genet. 2000; 30: 141-146
- A comparison between different designs and tests to detect QTLs in association studies.Behav Genet. 1999; 29: 245-256
- Linkage disequilibrium analysis of biallelic DNA markers, human quantitative trait loci, and threshold-defined case and control subjects.Am J Med Genet. 2000; 67: 1208-1218
- Iga972: A cross-platform application for optimizing LD studies using a genetic algorithm.Bioinformatics. 2004; 20: 3244-3245
- False discoveries and models for gene discovery.Trends Genet. 2003; 19: 537-542
- The future of association studies: Gene-based analysis and replication.Am J Med Genet. 2004; 75: 353-362
- Susceptibility genes for nicotine dependence: A genome scan and followup in an independent sample suggest that regions on chromosomes 2, 4, 10, 16, 17 and 18 merit further study.Mol Psychiatry. 1999; 4: 129-144
- Allelic discrimination using fluorogenic probes and the 5' nuclease assay.Genet Anal. 1999; 14: 143-149
- The International HapMap Project.Nature. 2003; 426: 789-796
- Haploview: Analysis and visualization of LD and haplotype maps.Bioinformatics. 2005; 21: 263-265
- Genetic association analysis of behavioral inhibition using candidate loci from mouse models.Am J Med Genet. 2001; 105: 226-235
- Reduced fear and aggression and altered serotonin metabolism in Gtf2ird1-targeted mice.Genes Brain Behav. 2008; 7: 224-234
- Metabolic control through the PGC-1 family of transcription coactivators.Cell Metab. 2005; 1: 361-370
- Meta-analysis of the Gly482Ser variant in PPARGC1A in type 2 diabetes and related phenotypes.Diabetologia. 2006; 49: 501-505
- Genome-wide association for major depressive disorder: A possible role for the presynaptic protein piccolo.Mol Psychiatry. 2009; 14: 359-375
- Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators.Cell. 2006; 127: 397-408
- PGC-1alpha deficiency causes multi-system energy metabolic derangements: Muscle dysfunction, abnormal weight control and hepatic steatosis.PLoS Biol. 2005; 3: e101
- Parvalbumin deficiency and GABAergic dysfunction in mice lacking PGC-1alpha.J Neurosci. 2010; 30: 7227-7235
Article info
Publication history
Published online: August 26, 2011
Accepted:
July 5,
2011
Received in revised form:
June 18,
2011
Received:
April 24,
2011
Identification
Copyright
© 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
