Carrasquillo, M. M. et al. Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer's disease. Nat. Genet. 41, 192-198

Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida 32224, USA.
Nature Genetics (Impact Factor: 29.35). 02/2009; 41(2):192-8. DOI: 10.1038/ng.305
Source: PubMed


By analyzing late-onset Alzheimer's disease (LOAD) in a genome-wide association study (313,504 SNPs, three series, 844 cases and 1,255 controls) and evaluating the 25 SNPs with the most significant allelic association in four additional series (1,547 cases and 1,209 controls), we identified a SNP (rs5984894) on Xq21.3 in PCDH11X that is strongly associated with LOAD in individuals of European descent from the United States. Analysis of rs5984894 by multivariable logistic regression adjusted for sex gave global P values of 5.7 x 10(-5) in stage 1, 4.8 x 10(-6) in stage 2 and 3.9 x 10(-12) in the combined data. Odds ratios were 1.75 (95% CI = 1.42-2.16) for female homozygotes (P = 2.0 x 10(-7)) and 1.26 (95% CI = 1.05-1.51) for female heterozygotes (P = 0.01) compared to female noncarriers. For male hemizygotes (P = 0.07) compared to male noncarriers, the odds ratio was 1.18 (95% CI = 0.99-1.41).

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    • "One chromosome that is especially over presented in women with AD is the X chromosome (Spremo-Potparevic et al., 2004, 2008; Zivkoví c et al., 2010; Bajic et al., 2015; Yurov et al., 2014). There is an increased prevalence of female susceptibility to AD than of men (Viña and Lloret, 2010; Carrasquillo et al., 2009) suggesting that, with the exception of perimenopausal women that have undergone hormonal changes (Casadesus et al., 2006, 2005), a possible alteration of the inactivation pattern or skewing (Bajic et al., 2015), PCD (Spremo-Potparevic et al., 2008) and aneuploidy (Yurov et al., 2015) may be related to AD pathogenesis. This instability phenotype has been proposed to be underlining mechanism of a process of accelerated aging in AD (Bají c et al., 2009). "
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    • "In the last decade, the role of the renin–angiotensin system (RAS) in the etiology of AD has received increasing attention. Inheritance of the I-allele – associated with lower plasma angiotensin-converting enzyme (ACE) levels [2] – was related to increased risk of AD [3,4], although these findings have not been supported by recent genome-wide association studies [5,6] and large haplotype studies [7]. Further, in vitro studies showed that ACE functions to degrade Aβ, and administration of ACE inhibitors promoted the accumulation of Aβ [8-10], while in vivo studies on various mouse models of AD showed indirect evidence that ACE can degrade Aβ (reviewed in [11]). "
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    ABSTRACT: Introduction Lower angiotensin-converting enzyme (ACE) activity could increase the risk of Alzheimer’s disease (AD) as ACE functions to degrade amyloid-β (Aβ). Therefore, we investigated whether ACE protein and activity levels in cerebrospinal fluid (CSF) and serum were associated with CSF Aβ, total tau (tau) and tau phosphorylated at threonine 181 (ptau). Methods We included 118 subjects from our memory clinic-based Amsterdam Dementia Cohort (mean age 66 ± 8 years) with subjective memory complaints (n = 40) or AD (n = 78), who did not use antihypertensive drugs. We measured ACE protein levels (ng/ml) and activity (RFU) in CSF and serum, and amyloid β1–42, tau and ptau (pg/ml) in CSF. Results Cross-sectional regression analyses showed that ACE protein level and activity in CSF and serum were lower in patients with AD compared to controls. Lower CSF ACE protein level, and to a lesser extent serum ACE protein level and CSF ACE activity, were associated with lower CSF Aβ, indicating more brain Aβ pathology; adjusted regression coefficients (B) (95% CI) per SD increase were 0.09 (0.04; 0.15), 0.06 (0.00; 0.12) and 0.05 (0.00; 0.11), respectively. Further, lower CSF ACE protein level was associated with lower CSF tau and ptau levels; adjusted B’s (95% CI) per SD increase were 0.15 (0.06; 0.25) and 0.17 (0.10; 0.25), respectively. Conclusions These results strengthen the hypothesis that ACE degrades Aβ. This could suggest that lowering ACE levels by for example ACE-inhibitors might have adverse consequences for patients with, or at risk for AD.
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    • "The development of genome-wide association studies (GWAS) has greatly improved AD genetic knowledge [152]. GWAS with fewer than 1000 cases or control subjects have implicated novel AD risk single nucleotide polymorphisms (SNPs) in GOLPH2, GAB2, and PCDH11X genes [153] [154] [155] [156]. More powerful, higher number case and control GWAS have identified or replicated novel AD risk SNPs in BIN1, CLU, CR1 and PICALM genes [157] [158] [159] [160] [161] [162] [163] [164], and a recent meta-analysis of GWAS identified a total of 20 genetic susceptibility loci (11 new genes, in addition to 9 previously-identified risk genes) [156]. "
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