Background Accumulating observational studies have suggested associations between imaging-derived phenotypes (IDPs) and common neurodegenerative disorders, especially Alzheimer’s disease (AD). The goal of this study is to evaluate the causal associations between structural and functional IDPs and 4 neurodegenerative disorders, including AD, Parkinson’s disease (PD), Amyotrophic lateral sclerosis (ALS), and Multiple sclerosis (MS).

Methods Bidirectional two-sample Mendelian randomization (MR) studies were conducted using summary statistics obtained from genome-wide association studies of 3909 IDPs from UK biobank and 4 neurodegenerative disorders.

Results Forward MR analysis showed that volume of cerebral white matter in the left hemisphere was associated with increased risk of ALS (odds ratio [OR] = 1.15, 95% confidence interval [CI] = 1.09-1.22, P = 3.52 x 10-6). In reverse MR analysis, we revealed genetically determined risk of AD and MS were associated with multiple IDPs (all P < 1.28 x 10-5[0.05/3909], 9 IDPs in AD and 4 IDPs in MS). For example, genetically determined risk of AD was causally associated with reduced volume of gray matter in right ventral striatum (OR = 0.95, 95% CI = 0.93-0.97, P = 4.68 x 10-7) and lower rfMRI amplitudes in several nodes (ICA25 node 9, ICA25 node 8, and ICA100 node 11). Additionally, genetically determined risk of MS was causally associated with reduced volume in left putamen (OR = 0.97, 95% CI = 0.97-0.98, P = 4.47 x 10-7) and increased orientation dispersion index in right hippocampus (OR = 1.03, 95% CI = 1.01-1.04, P = 2.02 x 10-6).

Conclusions Our study suggested plausible causal associations between risk of NDDs and brain IDPs. These findings might hold promise for identifying new disease mechanisms and developing novel preventative therapies for NDDs at the brain imaging levels.

The authors have declared no competing interest.

This work was supported by grants from National Natural Science Foundation of China (Grant No. 81873778, 82071415, and 82060213) and National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (Grant No. NRCTM(SH)-2021-03).

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Data availability GWAS statistics of brain IDPs were collected from BIG40 web browser (https://open.win.ox.ac.uk/ukbiobank/big40). Code availability All software packages we used in the study are publicly available, and the download links are included in the Methods section. The Code was available from the corresponding author upon reasonable request.