Genome-wide haplotype association study identify TNFRSF1A, CASP7, LRP1B, CDH1 and TG genes associated with Alzheimer's disease in Caribbean Hispanic individuals

Abstract

Alzheimer's disease (AD) is an acquired disorder of cognitive and behavioral impairment. It is considered to be caused by variety of factors, such as age, environment and genetic factors. In order to identify the genetic affect factors of AD, we carried out a bioinformatic approach which combined genome-wide haplotype-based association study with gene prioritization. The raw SNP genotypes data was downloaded from GEO database (GSE33528). It contains 615 AD patients and 560 controls of Caribbean Hispanic individuals. Firstly, we identified the linkage disequilibrium (LD) haplotype blocks and performed genome-wide haplotype association study to screen significant haplotypes that were associated with AD. Then we mapped these significant haplotypes to genes and obtained candidate genes set for AD. At last, we prioritized AD candidate genes based on their similarity with 36 known AD genes, so as to identify AD related genes. The results showed that 141 haplotypes on 134 LD blocks were significantly associated with AD (P<1E-4), and these significant haplotypes were mapped to 132 AD candidate genes. After prioritizing these candidate genes, we found seven AD related genes: APOE, APOC1, TNFRSF1A, LRP1B, CDH1, TG and CASP7. Among these genes, APOE and APOC1 are known AD risk genes. For the other five genes TNFRSF1A, CDH1, CASP7, LRP1B and TG, this is the first genetic association study which showed the significant association between these five genes and AD susceptibility in Caribbean Hispanic individuals. We believe that our findings can provide a new perspective to understand the genetic affect factors of AD.

Common variants ofNRXN1, LRP1BandRORAare associated with increased ventricular volumes in psychosis - GWAS findings from the B-SNIP deep phenotyping study

“…In our sample this quantitative phenotype measured in voxels by FreeSurfer was significantly different in cases vs. controls (ANOVA P=9.4E-05, Figure 2), with larger volumes for individuals with SZ than BP, which is consistent with findings from Shioiri et al [18]. One of the genes identified in association with the CSP volume, the LDL receptor related protein 1B, has been associated with Attention Deficit/Hyperactivity Disorder and Alzheimer's disease [22,44]. LRP1B is reported expressed in the adult and fetal brain [45] which, along with its association with an anatomical quantitative trait (CSP) of a persistent fetal structure, supports a role of this gene in a neurodevelopmental hypothesis of Bipolar Disorder and Schizophrenia [26].…”

“…NRXN1 encodes a large presynaptic transmembrane protein that binds neuroligins to calcium-dependent synaptic complexes in the central nervous system, and is also involved in the formation of synaptic contacts [21]. LRP1B is a candidate gene for Alzheimer's disease [22] and RORA is a candidate gene for PTSD [23]. coding RNA.…”

How understudied populations have contributed to our understanding of Alzheimer’s disease genetics

“…Since this report, a loss-of-function variant (rs10553596) has been reported to reduce the risk of AD in APOE E4 homozygotes83 . This haplotype association study also reported significant association between LRP1B, TNFRSF1A, CDH1, and TG, with AD susceptibility in Caribbean Hispanic individuals82 . Finally, the CASP7 rs116437863 variant has been significantly associated with familial LOAD in individuals of European ancestry 84 85.…”

“…Association of CASP7 with AD was first reported in a Caribbean Hispanic haplotype association study82 . Since this report, a loss-of-function variant (rs10553596) has been reported to reduce the risk of AD in APOE E4 homozygotes83 .…”

Early candidate urine biomarkers for detecting Alzheimer’s disease before beta amyloid plaque deposition in an APP (swe)/PSEN1dE9transgenic mouse model

“…To identify the differential proteins with mostly affected cellular death and survival, ingenuity pathway analysis (IPA) was applied to cell death and survival networks ( Figure 5). Cadherin-1, which was reported to be associated with AD [42], is a core component of these networks in 4-month-old mice.…”