Sex-specific genetic predictors of Alzheimer’s disease biomarkers

Abstract

Cerebrospinal fluid (CSF) levels of amyloid-β 42 (Aβ42) and tau have been evaluated as endophenotypes in Alzheimer's disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aβ42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aβ42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (β = - 0.03, p = 4.25 × 10; β = 0.03, p = 3.97 × 10) than males (β = - 0.02, p = 0.009; β = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values < 0.02) but not males (p > 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (β = 0.05, p = 4.57 × 10) compared to males (β = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (p = 0.047; p = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD's genetic architecture.

Biobank-wide association scan identifies risk factors for late-onset Alzheimer’s disease and endophenotypes

“…Still, small sample size made it challenging to assess the effects of traits that were weakly associated with AD. Finally, emerging evidence has highlighted sex-specific genetic architecture of AD [24, 33]. In our analysis, maternal family history of AD showed stronger associations with various phenotypes than paternal family history.…”

“…Maternal family history of AD and dementia was associated with ptau 181 (p=4.2e-4), but associations were absent for Aβ 42 and tau. It has been recently suggested that CSF biomarkers have sex-specific genetic architecture [24]. However, no association passed an FDR cutoff of 0.05 in sex-stratified analyses ( Supplementary Table 10 ).…”

“…GWAS of these subgroups is described in [20]; we analyzed the summary statistics from those analyses here. Detailed information about the design of CSF biomarker GWAS and the recent sex-stratified analysis has been described previously [23, 24]. Details on the association statistics for AD subgroups, CSF biomarkers, and neuropathological features are summarized in Supplementary Table 7 .…”

Sex differences in Alzheimer’s disease and common neuropathologies of aging

“…Indeed, a recent study showed that ubiquitin-specific peptidase 9 is a candidate gene with highly significant different expressions in women compared to men and is associated with expression and phosphorylation of tau [33]. Also, three genes were identified in a sex-stratified genome-wide association study that were associated with tau (Osteocrin and Claudin-16) and Aβ (Serpine Family B Member 1) only in women’s brain [18]. …”

Genome-wide association study of Alzheimer’s disease CSF biomarkers in the EMIF-AD Multimodal Biomarker Discovery dataset

“…Interestingly, association between markers in GMNC and CSF-Ttau levels were previously described [28] . A follow-up study to the original report provided evidence for sexspecific differences at this locus (rs1393060 proximal to GMNC and in strong LD with rs6444469 [r 2 =1]: P-value = 4.57E-10 in females compared to P-value = 0.03 in males) suggesting stronger effects in females [29]. In EMIF-AD MBD, we also observed a stronger association in females for GMNC at hence, providing independent replication of the previous report.…”