•Causal endophenotype inference with correlated SNPs boosts power over MR.•Multivariable instrumental variable regression accounts for horizontal pleiotropy.•Novel IWAS analogue to MR-Egger adjusts for remaining directional pleiotropy.•Integration of GWAS summary data for multiple heritable phenotypes.•Implicating genetically regulated MRI-derived brain measures in Alzheimer’s Disease.
Recent evidence suggests the existence of many undiscovered heritable brain phenotypes involved in Alzheimer’s Disease (AD) pathogenesis. This finding necessitates methods for the discovery of causal brain changes in AD that integrate Magnetic Resonance Imaging measures and genotypic data. However, existing approaches for causal inference in this setting, such as the univariate Imaging Wide Association Study (UV-IWAS), suffer from inconsistent effect estimation and inflated Type I errors in the presence of genetic pleiotropy, the phenomenon in which a variant affects multiple causal intermediate risk phenotypes. In this study, we implement a multivariate extension to the IWAS model, namely MV-IWAS, to consistently estimate and test for the causal effects of multiple brain imaging endophenotypes from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) in the presence of pleiotropic and possibly correlated SNPs. We further extend MV-IWAS to incorporate variant-specific direct effects on AD, analogous to the existing Egger regression Mendelian Randomization approach, which allows for testing of remaining pleiotropy after adjusting for multiple intermediate pathways. We propose a convenient approach for implementing MV-IWAS that solely relies on publicly available GWAS summary data and a reference panel. Through simulations with either individual-level or summary data, we demonstrate the well controlled Type I errors and superior power of MV-IWAS over UV-IWAS in the presence of pleiotropic SNPs. We apply the summary statistic based tests to 1578 heritable imaging derived phenotypes (IDPs) from the UK Biobank. MV-IWAS detected numerous IDPs as possible false positives by UV-IWAS while uncovering many additional causal neuroimaging phenotypes in AD which are strongly supported by the existing literature.