Widespread but moderate genetic overlap between circulating polyunsaturated fatty acids and brain disorders.

Abstract

Polyunsaturated fatty acids (PUFAs) are indispensable for proper neuronal function. PUFA deficiency and imbalance have been linked to various brain disorders, including major depressive disorder (MDD) and anxiety. However, the effects of PUFAs on brain disorders remain inconclusive, and the extent of their shared genetic determinants is largely unknown. We utilized genome-wide association summary statistics from six phenotypes of circulating PUFAs (N = 114,999) and 20 brain disorders (N = 9,725-762,917). We performed genome-wide analysis for each of the 120 trait pairs. We evaluated the correlation of genetic effects with genetic correlation, estimated the number of shared genetic variants with polygenic overlap, and prioritized potential causal relationships with two-sample Mendelian randomization (MR). We pinpointed specific shared variants with colocalization and statistical fine-mapping. Genetic correlation and polygenic overlap analyses revealed a widespread but moderate shared genetic basis for 77 PUFA-brain disorder trait pairs. MR suggested potential causal relationships for 16 pairs. Colocalization identified 40 shared loci (13 unique) and 22 candidate shared causal variants, including rs1260326 (GCKR), rs174564 (FADS2), and rs4818766 (ADARB1). These genes were mapped to lipid metabolism pathways. Integrating evidence from multiple approaches, we prioritized four PUFA-brain disorder pairs with potential causal links, including PUFA% with MDD, and omega-6% with alcohol consumption. These findings reveal a widespread but moderate shared genetic basis between PUFAs and brain disorders, pinpoint specific shared variants, and provide support for potential effects of PUFAs on certain brain disorders, especially MDD and alcohol consumption. Future studies are needed to elucidate potential causal effects.