Effects of MS4A variants on cerebrospinal fluid beta-amyloid 1-42

Abstract

Listen

Translate article

Single nucleotide polymorphisms (SNPs) in the membrane-spanning 4-domains, subfamily A (MS4A) gene cluster have been identified in genome-wide association studies (GWAS) to be associated with Alzheimer's disease (AD). We recently reported that MS4A4A rs2304933, but not MS4A4E rs670139 and MS4A6A rs2304933, significantly reduced cerebrospinal fluid (CSF) amyloid beta 1–42 isoform (A b 1–42) in a Finnish AD population. We aim to replicate these findings in an independent cohort composed of various diagnostic groups. We included 243 participants (78 AD, 93 mild cognitive impairment, 48 other type of dementia, 24 cognitively healthy control subjects) from the European multicentre EDAR study. Genomic DNA was extracted from EDTA anticoagulated blood and was amplified by polymerase chain reaction (PCR). We genotyped MS4A4E rs670139, MS4A6A rs610932 and MS4A4A rs2304933 on the Sequenom I-plex platform. CSF was obtained through lumbar puncture and analysed using multiplex xMAP Luminex platform. Statistical analyses were performed using mixed models, corrected for age, sex, APOE - e 4 status and study site. Adjustment for multiple testing was set at a false discovery rate adjusted P<0.05. The mean CSF A b 1–42 levels of homozygote risk allele carriers were lower compared to other genotypes for all SNPs. Variant rs610932 was associated with decreased CSF A b 1–42concentration (unadjusted P =0.001, FDR adjusted P<0.05) in a dominant model. A trend of decreased CSF A b 1–42levels were observed for rs670139 (unadjusted P =0.12) and rs2304933 (unadjusted P =0.08) in a recessive model. There was no interaction with age, sex, APOE - e 4 status and diagnosis for all analyses (all P>0.05). Our findings suggest that polymorphisms in the MS4A gene influence CSF A b 1- 42 concentrations. This supports results from GWAS studies that this gene is a genetic risk factor for AD.