Early origins of neurological disorders: Mendelian randomization evidence for a causal relationship between low birth weight and multiple sclerosis

With the deepening of global aging and neurological disorders having become the second leading cause of death and primary cause of disability worldwide, the prevention of neurological disorders has emerged as an increasingly critical issue. This study employed a two-sample Mendelian randomization (MR) analysis to evaluate the causal associations between birth weight and risk of 6 common neurological disorders, thereby providing genetic epidemiological evidence for the early origins hypothesis of neurological disorders.

This study utilized publicly available genome-wide association study summary statistics. Genetic variants significantly associated with birth weight were selected as instrumental variables to construct two instrumental variable sets comprising 7-single nucleotide polymorphism (SNP) and 60-SNP, respectively. The two-sample MR outcomes included Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis, epilepsy, migraine, and cerebrovascular disease, with all relevant data obtained from publicly available datasets on the OpenGWAS platform. Inverse variance weighting was used as the primary analysis, with robustness validation by MR-Egger, weighted median, simple mode, and weighted mode methods. Heterogeneity and horizontal pleiotropy were assessed using Cochran's Q test, horizontal pleiotropy test, leave-one-out analysis, and funnel plots.

In the 7-SNP analysis, genetically predicted low birth weight was associated with an increased risk of multiple sclerosis, with an OR of 1. 323 (95%CI: 1. 011 to 1. 732, P=0. 041) obtained using inverse variance weighting. No significant causal relationships were observed for the remaining 5 neurological disorders (AD, PD, migraine, cerebrovascular disease, and epilepsy). In the 60-SNP analysis, the findings for multiple sclerosis were consistent in direction with the aforementioned association and remained statistically significant, yielding an OR value of 1. 319 (95%CI: 1. 006 to 1. 731, P=0. 045) by inverse variance weighting. Although PD showed negative association effects in the weighted median and weighted mode methods, the results of inverse variance weighting did not reach significance (OR=0. 811, 95%CI: 0. 608 to 1. 081, P=0. 154). There were no significant causal relationships for the remaining 4 neurological disorders (AD, cerebrovascular disease, epilepsy, and migraine). Sensitivity analyses for multiple sclerosis did not indicate significant systematic pleiotropy in either the 7-SNP and 60-SNP models; heterogeneity increased after expanding from 7-SNP to 60-SNP, but leave-one-out analysis demonstrated that the pooled effect was not driven by any single SNP.

Genetic evidence supports a potential causal relationship between low birth weight and an increased risk of multiple sclerosis, whereas no clear causal relationships are identified with AD, epilepsy, migraine, PD, or cerebrovascular disease.