Brainwide Mendelian Randomization Study of Anxiety Disorders and Symptoms

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 (3 = -0.09, p = 8.01 X 10 -4 ) and reduced gray matter volume of the right anterior superior temporal gyrus (3 = -0.09, p = 1.55 X 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" (3 = -0.13, p = 8.26 X 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.