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[O1–03–05]: ANNOTATION‐STRATIFIED GENETIC CORRELATION ANALYSIS IDENTIFIES SHARED AND DISTINCT GENETIC ARCHITECTURE OF LATE‐ONSET ALZHEIMER's DISEASE AND AMYOTROPHIC LATERAL SCLEROSIS
Author(s) -
Lu Qiongshi,
Mukherjee Shubhabrata,
Crane Paul K.,
Zhao Hongyu
Publication year - 2017
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2017.07.049
Subject(s) - genome wide association study , genetic architecture , amyotrophic lateral sclerosis , biology , genetic association , quartile , single nucleotide polymorphism , covariance , computational biology , genetic correlation , genetics , correlation , genetic variation , statistics , disease , medicine , quantitative trait locus , genotype , mathematics , gene , geometry , pathology , confidence interval
ical region, MAF1⁄40.26, P1⁄41.5x10). The top XWAS-hit rs112930037, near DCAF12L2, was successfully replicated in the SEE cohort (P1⁄40.018). rs112930037 increases risk for LOAD in both males and in females (males OR1⁄41.216, P1⁄40.011; females OR1⁄41.314, P1⁄46.0x10). Gene-based analysis failed to reveal genes associated with LOAD. Conclusions: Our study reveals the existence of an X-linked locus for LOAD on Xq25 DCAF12L2, which is one of the only two known retrogenes on the X chromosome and widely expressed in the brain. The parent gene DCAF12, located on 9p13.3 (a frontotemporal dementia linkage region), encodes a WD repeat-containing protein that interacts with the COP9 signalosome. Recent studies reveal that members of the COP9 signalosome were associated with several neurological disorders, including AD. By interacting with its parent gene DCAF12L2 may influence COP9 signalosome activity, thereby playing a role in dendritic morphogenesis as previously described in the Drosophila literature. Further studies will address the functional impact of genetic variation at the Xq25 locus in influencing susceptibility to LOAD.