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COMPLEMENT FACTOR CSMD1 IS ASSOCIATED WITH NEOCORTICAL LEWY BODY COUNT IN A JAPANESE-AMERICAN POPULATION-BASE AUTOPSY SERIES: THE HONOLULU-ASIA AGING STUDY
Abstract
Aims
To test the hypothesis that genome wide association studies (GWASs) of the lesions underlying clinical neurological syndromes are a powerful way to uncover the molecular etiology of disease.
Methods
Case material are 308 autopsies of Japanese-American men (mean age at death 87.5 years; 11% with mild, and 30% with severe cognitive impairment prior to death). Lewy bodies were assessed by manual count of alpha-synuclein stained neocortical sections from the frontal, temporal, parietal, and occipital lobes. Genetic association was tested by linear models controlling for age at death assuming an additive genotypic effect.
Results
Top hits include a locus on chromosome 1q32 previously associated with amyotrophic lateral sclerosis (p=5.8e-8), intronic variants on the dopaminergic neuron axonal guidance gene EPHB1 previously associated with Parkinson’s disease (PD) (p=8.4e-6), and a locus containing two independent intron 1 variants on CSMD1, a known risk factor for autosomal dominant PD (p=1.5e-6). Complement inhibitor protein CSMD1 is a type 1 transmembrane cell adhesion molecule implicated in axonal guidance and the development, maintenance, and pruning of synapses in the adult brain. Intermediate hits include genes encoding cell adhesion molecules and a second complement inhibitor implicated in the regulation of synapses (TRAPPC9).
Conclusions
This converging evidence points to cell adhesion proteins and complement mediated synaptic regulation in the etiology of Lewy body lesions. The clear relevance of genes identified confirms the hypothesis that GWAS of neuropathologic endophenotypes is a valid and statistically powerful approach to discovering risk factor genes that moreover directly informs our understanding of the molecular pathways underlying disease.