Local genetic correlations exist among neurodegenerative and neuropsychiatric diseases

Abstract Genetic correlation ( $$r_g$$ r g ) between traits can offer valuable insight into underlying shared biological mechanisms. Neurodegenerative diseases overlap neuropathologically and often manifest comorbid neuropsychiatric symptoms. However, global $$r_g$$ r g analyses show minimal $$r_g$$ r g among neurodegenerative and neuropsychiatric diseases. Importantly, local $$r_g$$ r g s can exist in the absence of global relationships. To investigate this possibility, we applied LAVA, a tool for local $$r_g$$ r g analysis, to genome-wide association studies of 3 neurodegenerative diseases (Alzheimer’s disease, Lewy body dementia and Parkinson’s disease) and 3 neuropsychiatric disorders (bipolar disorder, major depressive disorder and schizophrenia). We identified several local $$r_g$$ r g s missed in global analyses, including between (i) all 3 neurodegenerative diseases and schizophrenia and (ii) Alzheimer’s and Parkinson’s disease. For those local $$r_g$$ r g s identified in genomic regions containing disease-implicated genes, such as SNCA, CLU and APOE, incorporation of expression quantitative trait loci identified genes that may drive genetic overlaps between diseases. Collectively, we demonstrate that complex genetic relationships exist among neurodegenerative and neuropsychiatric diseases, highlighting putative pleiotropic genomic regions and genes. These findings imply sharing of pathogenic processes and the potential existence of common therapeutic targets.