(P10-028-23) Shared Genetic Basis Informs the Roles of Polyunsaturated Fatty Acids in Brain Disorders

Objectives: To examine the shared genetic basis between the circulating levels of polyunsaturated fatty acids (PUFAs) and brain disorders, and to infer their causal relationships.

Methods: We performed four major analyses using genome-wide association study summary statistics for 11 circulating PUFA levels (n=114,999) and 20 brain disorders (n=9,725~762,917). The 11 PUFA traits include total PUFAs, omega-3, omega-6, LA, DHA, and their relative percentages in total fatty acids. First, we performed genetic correlation (r_g) analysis with LD score regression (LDSC). Second, we applied MiXeR to quantify the proportion of shared causal genetic variants. Third, we applied Mendelian randomization (MR) analysis using TwoSampleMR to infer causal relationships. Lastly, we performed genome-wide statistical fine-mapping using SuSiE to pinpoint the candidate shared variants.

Results: First, our LDSC analysis revealed a widespread and moderate genetic correlation between most brain disorders and the relative PUFA measures. PUFA%, omega-6%, omega-3%, LA%, and DHA% have significant negative correlation with opioid dependence (r_g=-0.4~-0.23, P < 0.05), alcohol dependence, (r_g=-0.3~-0.18, P < 0.05) and cannabis use disorders (r_g=-0.27~-0.20, P < 0.001). Moreover, these PUFA measures are positively correlated with obsessive-compulsive disorder (r_g=0.14~0.3, P < 0.05) and anorexia nervosa (r_g=0.16~0.27, P < 2.27E-04). Second, MiXeR provided the estimated proportions of causal genetic overlap in ~11 million variants examined. They ranged from 17 variants between omega-3% and Alzheimer’s disease to 1,243 between PUFA% and MDD. Third, our forward MR analysis identified 18 pairs in which the PUFA measure may causally increase the brain disorder risk, and 12 pairs in which PUFAs reduce the risk. Lastly, our statistical fine-mapping pinpointed candidate, shared, causal variants. For instance, rs1260326, a missense variant for gene GCKR, has potential causal effects on PUFA% (β=0.09, P = 9.79e-113) and alcohol consumption (β=0.007, P = 5.47e-09).

Conclusions: Our systemic genetic analysis of 11 PUFA traits and 20 brain disorders revealed a widespread shared genetic basis between the two groups, pinpointed specific shared genetic variants, and provided support for potential causal effects of PUFAs on certain brain disorders.

Funding Sources: This study was supported by NIGMS.