A Mendelian randomization approach to characterize overlap in the pathophysiology of neurological disorders

Abstract

AbstractBackgroundNeurodegenerative diseases are characterized by progressive neuronal death, leading to loss of cognitive function. This process is thought to commence decades before symptom onset. Consequently, there is a dire need to characterize the pre‐clinical phase of neurodegenerative diseases to provide early intervention. We employed a Mendelian randomization approach to identify genetic overlap across neurological disorders and describe common disease mechanisms.MethodWe utilized our web‐based multi‐omics analytic tool ONTIME (Online Neurodegenerative Trait Integrative Multi‐Omics Explorer, http://ngi.pub/ONTIME/) to apply two‐sample Mendelian randomization to neurological disorders. We estimated the causal effect of 59 cerebrospinal fluid (CSF) analytes and 134 plasma analytes on the risk of Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic Lateral Sclerosis (ALS), and stroke. Instrumental variables for CSF (N = 672) and plasma (N = 818) analytes were obtained from quantitative genome‐wide association studies we performed using the RBM Human DiscoveryMAP panel.ResultIn CSF, we identified seven analytes that have a causal effect on AD, two analytes that have a causal effect on ALS, and three analytes that have a causal effect on stroke after false discovery rate (FDR) adjustment (Table 1). In plasma, we identified eleven analytes that have a causal effect on AD, eight analytes that have a causal effect on ALS, and five analytes that have a causal effect on stroke after FDR adjustment (Table 2). Furthermore, we detected overlap in the pathogenesis of AD and ALS as well as AD and stroke.ConclusionOur results support a growing body of evidence that there is significant genetic and pathophysiological overlap across neurodegenerative diseases. Furthermore, our findings provide evidence that vascular factors contribute to neurodegenerative disease onset. Finally, these results highlight the utility of ONTIME and its Mendelian randomization tool. Users can upload disease summary statistics and test if any CSF or plasma analyte in our catalogue has a causal effect on their uploaded health outcomes.