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. 2024 Apr 15;95(8):810-817.
doi: 10.1016/j.biopsych.2023.11.006. Epub 2023 Nov 14.

Brainwide Mendelian Randomization Study of Anxiety Disorders and Symptoms

Mihaela-Diana Zanoaga  1 , Eleni Friligkou  2 , Jun He  2 , Gita A Pathak  2 , Dora Koller  3 , Brenda Cabrera-Mendoza  2 , Murray B Stein  4 , Renato Polimanti  5
Affiliations

Brainwide Mendelian Randomization Study of Anxiety Disorders and Symptoms

Mihaela-Diana Zanoaga et al. Biol Psychiatry. .

Abstract

Background: To gain insights into the role of brain structure and function on anxiety (ANX), we conducted a genetically informed investigation leveraging information from ANX genome-wide association studies available from the UK Biobank (n = 380,379), the FinnGen Program (n = 290,361), and the Million Veteran Program (n = 175,163) together with UK Biobank genome-wide data (n = 33,224) related to 3935 brain imaging-derived phenotypes (IDPs).

Methods: A genetic correlation analysis between ANX and brain IDPs was performed using linkage disequilibrium score regression. To investigate ANX-brain associations, a 2-sample Mendelian randomization was performed considering multiple methods and sensitivity analyses. A subsequent multivariable Mendelian randomization was conducted to distinguish between direct and indirect effects. Finally, a generalized linear model was used to explore the associations of brain IDPs with ANX symptoms.

Results: After false discovery rate correction (q < .05), we identified 41 brain IDPs genetically correlated with ANX without heterogeneity among the datasets investigated (i.e., UK Biobank, FinnGen, and Million Veteran Program). Six of these IDPs showed genetically inferred causal effects on ANX. In the subsequent multivariable Mendelian randomization analysis, reduced area of the right posterior middle cingulate gyrus (β = -0.09, p = 8.01 × 10-4) and reduced gray matter volume of the right anterior superior temporal gyrus (β = -0.09, p = 1.55 × 10-3) had direct effects on ANX. In the ANX symptom-level analysis, the right posterior middle cingulate gyrus was negatively associated with "tense, sore, or aching muscles during the worst period of anxiety" (β = -0.13, p = 8.26 × 10-6).

Conclusions: This study identified genetically inferred effects that are generalizable across large cohorts, thereby contributing to our understanding of how changes in brain structure and function can lead to ANX.

Keywords: Brain function; Brain structure; Causal inference; Genome-wide association studies; Pleiotropy.

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Conflict of interest statement

DISCLOSURES

RP received a research grant from Alkermes and is paid for his editorial work on the journal Complex Psychiatry. MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, atai Life Sciences, Boehringer Ingelheim, Bionomics, BioXcel Therapeutics, Clexio, Delix Pharmaceuticals, EmpowerPharm, Engrail Therapeutics, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech; has stock options in Oxeia Biopharmaceuticals and EpiVario; and has been paid for editorial work on Depression and Anxiety (Editor-in-Chief), Biological Psychiatry (Deputy Editor), and UpToDate (Co-Editor-in-Chief for Psychiatry). All other authors report no biomedical financial interests or potential conflicts of interest.

Figures

Figure 1.
Figure 1.. Genetic correlation between ANX and brain IDP surviving false discovery rate multiple testing correction in the cross-cohort meta-analysis (FDR q<0.05).
Full description of the brain IDPs and their genetic correlation statistics are available in Supplemental Table 4.
Figure 2.
Figure 2.. Genetically inferred effect of brain IDPs on ANX.
We report the inverse-weighted variance estimates of the betas and 95% confidence intervals (CI) obtained from the two-sample Mendelian randomization (MR). T1 FAST ROIs R sup temp gyrus ant: (IDP 0043); aparc-Desikan rh area superior-frontal: (IDP 0709); aparc-a2009s rh area G+S-cingul-Mid-Ant (IDP 0952); aparc-a2009s rh area G+S-cingul-Mid-Post (IDP 0953); T2 FLAIR BIANCA WMH volume (IDP 1437); dMRI ProbtrackX FA fmi (IDP 1511); dMRI ProbtrackX ICVF fmi (IDP 1961); rfMRI connectivity ICA-features 2 (IDP 3915). Details of MR results and a description of the brain IDPs are available in Supplemental Table 5.
Figure 3.
Figure 3.. Genetically inferred direct effect of brain IDPs on ANX identified by the multivariable Mendelian randomization analysis (MVMR).
IDPs with significant MVMR estimates are indicated in bright orange with red arrows. T1 FAST ROIs R sup temp gyrus ant: (IDP 0043); aparc-a2009s rh area G+S-cingul-Mid-Post (IDP 0953); T2 FLAIR BIANCA WMH volume (IDP 1437); dMRI ProbtrackX FA fmi (IDP 1511); dMRI ProbtrackX ICVF fmi (IDP 1961); rfMRI connectivity ICA-features 2 (IDP 3915). Details of MVMR results and description of the brain IDPs are available in Supplemental Table 9.
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