Genetic Association of Sequence Variants Near AGER/NOTCH4 and Dementia

We performed a survey of sequence variation in a series of 20 genes involved in inflammation-related pathways for association with dementia risk in twin and unrelated case-control samples consisting in total of 1462 Swedish dementia cases and 1929 controls. For a total of 218 tested genetic markers, strong evidence was obtained implicating a region near AGER and NOTCH4 on chromosome 6p with replication across both samples and maximum combined significance at marker rs1800625 (OR = 1.37, 95% CI 1.19-1.56, p = 1.36x10(-6)). Imputation of the associated genomic interval provided an improved signal at rs8365, near the 3'UTR of AGER (p = 7.34x10(-7)). The associated region extends 120 kb encompassing 11 candidate genes. While AGER encodes a key receptor for amyloid-beta protein, an analysis of network context based upon genes now confirmed to contribute to dementia risk (A beta PP, PSEN1, PSEN2, CR1, CLU, PICALM, and APOE) suggested strong functional coupling to NOTCH4, with no significant coupling to the remaining candidates. The implicated region occurs in the broad HLA locus on chromosome 6p, but associated markers were not in strong LD with known variants that regulate HLA gene function, suggesting that this may represent a signal distinct from immune-system pathways.