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. 2020 Dec;25(12):3292-3303.
doi: 10.1038/s41380-019-0559-1. Epub 2019 Nov 20.

A major role for common genetic variation in anxiety disorders

Kirstin L Purves  1 , Jonathan R I Coleman  1   2 , Sandra M Meier  3   4   5 , Christopher Rayner  1 , Katrina A S Davis  2   6 , Rosa Cheesman  1 , Marie Bækvad-Hansen  5   7 , Anders D Børglum  5   8   9 , Shing Wan Cho  1 , J Jürgen Deckert  10 , Héléna A Gaspar  1   2 , Jonas Bybjerg-Grauholm  5   7 , John M Hettema  11 , Matthew Hotopf  2   6 , David Hougaard  5   7 , Christopher Hübel  1   2   12 , Carol Kan  13 , Andrew M McIntosh  14   15 , Ole Mors  4   5 , Preben Bo Mortensen  5   9   16 , Merete Nordentoft  5   17 , Thomas Werge  5   18   19 , Kristin K Nicodemus  20 , Manuel Mattheisen  5   8   10   21 , Gerome Breen #  22   23 , Thalia C Eley #  24   25
Affiliations

A major role for common genetic variation in anxiety disorders

Kirstin L Purves et al. Mol Psychiatry. 2020 Dec.

Abstract

Anxiety disorders are common, complex psychiatric disorders with twin heritabilities of 30-60%. We conducted a genome-wide association study of Lifetime Anxiety Disorder (ncase = 25 453, ncontrol = 58 113) and an additional analysis of Current Anxiety Symptoms (ncase = 19 012, ncontrol = 58 113). The liability scale common variant heritability estimate for Lifetime Anxiety Disorder was 26%, and for Current Anxiety Symptoms was 31%. Five novel genome-wide significant loci were identified including an intergenic region on chromosome 9 that has previously been associated with neuroticism, and a locus overlapping the BDNF receptor gene, NTRK2. Anxiety showed significant positive genetic correlations with depression and insomnia as well as coronary artery disease, mirroring findings from epidemiological studies. We conclude that common genetic variation accounts for a substantive proportion of the genetic architecture underlying anxiety.

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Figures

Figure 1.
Figure 1.. Manhattan and Q-Q plots for UK Biobank anxiety analyses
Manhattan and Q-Q plots of p-values of Single Nucleotide Polymorphisms (SNP) based association analyses of anxiety in the UK Biobank. In the Manhattan plots, the threshold for genome-wide significance (p < 5×10−08) Is indicated by the red line, while the blue line indicates the threshold for suggestive significance (p < 1×10−5). Top panel showing results for our core Lifetime Anxiety Disorder analysis. Bottom panel showing results for the Current Anxiety Symptoms analysis.
Figure 2.
Figure 2.. Genetic correlations between UK Biobank Lifetime Anxiety Disorder and significantly associated external traits
Figure showing genetic correlations (rG) between UK Biobank “Lifetime Anxiety Disorder” and external phenotypes generated from LDhub. Only traits where correlation exceeded Bonferroni corrected threshold of p < 0.0002 shown here. Depression and neuroticism were not included in this analysis as they have been included as replication samples in subsequent analyses. See supplementary table 7 for rG with the latest publically available neuroticism and MDD GWAS samples including UK Biobank. Asterisks (*) Indicates source study sample wholly or partially included UK Biobank participants. Correlations ordered first by rG within category. Bars show standard error of the estimate.
Figure 3.
Figure 3.. Gene Manhattan plot with top significant gene per chromosome
Manhattan plots of p-values of gene-wise association analyses of “Lifetime Anxiety Disorder” in the UK Biobank. In the Manhattan plots, the threshold for gene-wide significance (p < 3×10–06) Is indicated by the red line, while the blue line indicates the threshold for suggestive significance (p < 1×10–5)
Figure 4.
Figure 4.. Manhattan and Q-Q plots for meta-analysis of all Lifetime Anxiety Disorder samples
Manhattan and Q-Q plots of p-values of Single Nucleotide Polymorphisms (SNP) based association analyses of combined sample meta-analysis across three Lifetime Anxiety Disorder cohorts (UK Biobank, ANGST and iPSYCH). In the Manhattan plots, the threshold for genome-wide significance (p < 5×10–08) Is indicated by the red line, while the blue line indicates the threshold for suggestive significance (p < 1×10–5)
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