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- Haiman, Christopher A., et al.
(författare)
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A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:12, s. 61-1210
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 x 10(-10)). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 x 10(-9)), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 x 10(-9)). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations.
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- Heston, M. B., et al.
(författare)
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Gut inflammation associated with age and Alzheimer's disease pathology: a human cohort study
- 2023
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Ingår i: Scientific Reports. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Age-related disease may be mediated by low levels of chronic inflammation ("inflammaging"). Recent work suggests that gut microbes can contribute to inflammation via degradation of the intestinal barrier. While aging and age-related diseases including Alzheimer's disease (AD) are linked to altered microbiome composition and higher levels of gut microbial components in systemic circulation, the role of intestinal inflammation remains unclear. To investigate whether greater gut inflammation is associated with advanced age and AD pathology, we assessed fecal samples from older adults to measure calprotectin, an established marker of intestinal inflammation which is elevated in diseases of gut barrier integrity. Multiple regression with maximum likelihood estimation and Satorra-Bentler corrections were used to test relationships between fecal calprotectin and clinical diagnosis, participant age, cerebrospinal fluid biomarkers of AD pathology, amyloid burden measured using 11C-Pittsburgh compound B positron emission tomography (PiB PET) imaging, and performance on cognitive tests measuring executive function and verbal learning and recall. Calprotectin levels were elevated in advanced age and were higher in participants diagnosed with amyloid-confirmed AD dementia. Additionally, among individuals with AD dementia, higher calprotectin was associated with greater amyloid burden as measured with PiB PET. Exploratory analyses indicated that calprotectin levels were also associated with cerebrospinal fluid markers of AD, and with lower verbal memory function even among cognitively unimpaired participants. Taken together, these findings suggest that intestinal inflammation is linked with brain pathology even in the earliest disease stages. Moreover, intestinal inflammation may exacerbate the progression toward AD.
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- Dumitrescu, L., et al.
(författare)
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Sex differences in the genetic predictors of Alzheimer's pathology
- 2019
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 142, s. 2581-2589
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Tidskriftsartikel (refereegranskat)abstract
- Autopsy measures of Alzheimer's disease neuropathology have been leveraged as endophenotypes in previous genome-wide association studies (GWAS). However, despite evidence of sex differences in Alzheimer's disease risk, sex-stratified models have not been incorporated into previous GWAS analyses. We looked for sex-specific genetic associations with Alzheimer's disease endophenotypes from six brain bank data repositories. The pooled dataset included 2701 males and 3275 females, the majority of whom were diagnosed with Alzheimer's disease at autopsy (70%). Sex-stratified GWAS were performed within each dataset and then meta-analysed. Loci that reached genome-wide significance (P < 5 x 10(-8)) in stratified models were further assessed for sex interactions. Additional analyses were performed in independent datasets leveraging cognitive, neuroimaging and CSF endophenotypes, along with age-at-onset data. Outside of the APOE region, one locus on chromosome 7 (rs34331204) showed a sex-specific association with neurofibrillary tangles among males (P = 2.5 x 10(-8)) but not females (P = 0.85, sex-interaction P = 2.9 x 10(-4)). In follow-up analyses, rs34331204 was also associated with hippocampal volume, executive function, and age-at-onset only among males. These results implicate a novel locus that confers male-specific protection from tau pathology and highlight the value of assessing genetic associations in a sex-specific manner.
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- Deming, Yuetiva, et al.
(författare)
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Sex-specific genetic predictors of Alzheimer’s disease biomarkers
- 2018
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 136:6, s. 857-872
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Tidskriftsartikel (refereegranskat)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 × 10−8; β = 0.03, p = 3.97 × 10−8) 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 × 10−10) compared to males (β = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale = 0.047; pmale = 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.
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- Panyard, D. J., et al.
(författare)
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Large-scale proteome and metabolome analysis of CSF implicates altered glucose and carbon metabolism and succinylcarnitine in Alzheimer's disease
- 2023
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Ingår i: Alzheimers & Dementia. - 1552-5260.
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTIONA hallmark of Alzheimer's disease (AD) is the aggregation of proteins (amyloid beta [A] and hyperphosphorylated tau [T]) in the brain, making cerebrospinal fluid (CSF) proteins of particular interest. METHODSWe conducted a CSF proteome-wide analysis among participants of varying AT pathology (n = 137 participants; 915 proteins) with nine CSF biomarkers of neurodegeneration and neuroinflammation. RESULTSWe identified 61 proteins significantly associated with the AT category (P < 5.46 x 10(-5)) and 636 significant protein-biomarker associations (P < 6.07 x 10(-6)). Proteins from glucose and carbon metabolism pathways were enriched among amyloid- and tau-associated proteins, including malate dehydrogenase and aldolase A, whose associations with tau were replicated in an independent cohort (n = 717). CSF metabolomics identified and replicated an association of succinylcarnitine with phosphorylated tau and other biomarkers. DISCUSSIONThese results implicate glucose and carbon metabolic dysregulation and increased CSF succinylcarnitine levels with amyloid and tau pathology in AD. HIGHLIGHTSCerebrospinal fluid (CSF) proteome enriched for extracellular, neuronal, immune, and protein processing.Glucose/carbon metabolic pathways enriched among amyloid/tau-associated proteins.Key glucose/carbon metabolism protein associations independently replicated.CSF proteome outperformed other omics data in predicting amyloid/tau positivity.CSF metabolomics identified and replicated a succinylcarnitine-phosphorylated tau association.
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| 9. |
- Thorstenson, J. C., et al.
(författare)
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Diet and APOE as moderators of the relationship between trimethylamine N-oxide and biomarkers of Alzheimer's disease and glial activation
- 2021
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 17
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Dietary patterns appear to impact cognitive trajectories in aging, and gut microbiota have been implicated in Alzheimer's disease (AD) pathogenesis, potentially as modulators of neuroinflammation early in the disease. Diets featuring low meat and dairy consumption have been linked to reduced AD risk, and recently, the gut microbial metabolite trimethylamine N-oxide (TMAO) was found in cerebrospinal fluid (CSF) and linked to CSF biomarkers of AD. Because TMAO is largely derived from dietary sources of choline, carnitine, and betaine, we examined whether these precursors drive the association between TMAO and sTREM2, a marker for glial activation. Additionally, TMAO has been found to inhibit cholesterol metabolism, a strong risk factor for AD, which is further dysregulated by the APOE4 allele. Therefore, we aimed to determine whether TMAO-glial activation relationships are moderated by APOE4 carrier status. METHOD: Participants from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center provided CSF samples (n=570, Table 1). sTREM2 and YKL-40 biomarkers were measured with the exploratory Roche NeuroToolKit assays, a panel of robust prototype immunoassays (Roche Diagnostics International Ltd). TMAO, carnitine, choline, and betaine relative abundance were obtained using Metabolon's UHPLC-MS/MS metabolomics platform. A subset of participants (n=159) completed the MIND diet questionnaire. Metabolite and biomarker levels were log-transformed for analysis; models were adjusted for age, sex, and APOE4 carrier status. Linear regression tested associations between intake of TMAO precursor-containing foods (red meat, butter, cheese, fish) and CSF levels of each TMAO precursor. Path analysis with Satorra-Bentler adjustments tested whether TMAO mediated precursor-biomarker relationships. Linear regression tested whether APOE4 carrier status moderated TMAO-biomarker relationships. RESULT: Red meat and cheese consumption predicted levels of CSF carnitine (βs=0.009, -0.017; ps=0.0609, 0.0007; Figure 1 A, B; respectively). TMAO mediated the relationship between carnitine and sTREM2, although effects were marginal; several individual relationships throughout both path models showed strong associations (Tables 2, 3; Figures 2, 3). APOE4 carrier status did not significantly moderate TMAO-glial activation relationships. CONCLUSION: This study suggests that CSF carnitine reflects dietary intake, and may drive the TMAO-sTREM2 association previously identified. Future studies in animal models are required to confirm these results mechanistically. © 2021 the Alzheimer's Association.
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- Morrow, A., et al.
(författare)
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Cerebrospinal Fluid Sphingomyelins in Alzheimer's Disease, Neurodegeneration, and Neuroinflammation
- 2022
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Ingår i: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 90:2, s. 667-680
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Tidskriftsartikel (refereegranskat)abstract
- Background: Sphingomyelin (SM) levels have been associated with Alzheimer's disease (AD), but the association direction has been inconsistent and research on cerebrospinal fluid (CSF) SMs has been limited by sample size, breadth of SMs examined, and diversity of biomarkers available. Objective: Here, we seek to build on our understanding of the role of SM metabolites in AD by studying a broad range of CSF SMs and biomarkers of AD, neurodegeneration, and neuroinflammation. Methods: Leveraging two longitudinal AD cohorts with metabolome-wide CSF metabolomics data (n = 502), we analyzed the relationship between the levels of 12 CSF SMs, and AD diagnosis and biomarkers of pathology, neurodegeneration, and neuroinflammation using logistic, linear, and linear mixed effects models. Results: No SMs were significantly associated with AD diagnosis, mild cognitive impairment, or amyloid biomarkers. Phosphorylated tau, neurofilament light, alpha-synuclein, neurogranin, soluble triggering receptor expressed on myeloid cells 2, and chitinase-3-like-protein 1 were each significantly, positively associated with at least 5 of the SMs. Conclusion: The associations between SMs and biomarkers of neurodegeneration and neuroinflammation, but not biomarkers of amyloid or diagnosis of AD, point to SMs as potential biomarkers for neurodegeneration and neuroinflammation that may not be AD-specific.
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| 11. |
- Panyard, D. J., et al.
(författare)
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Liver-Specific Polygenic Risk Score Is Associated with Alzheimer's Disease Diagnosis
- 2023
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Ingår i: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 92:2, s. 395-409
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Tidskriftsartikel (refereegranskat)abstract
- Background: Our understanding of the pathophysiology underlying Alzheimer's disease (AD) has benefited from genomic analyses, including those that leverage polygenic risk score (PRS) models of disease. The use of functional annotation has been able to improve the power of genomic models. Objective: We sought to leverage genomic functional annotations to build tissue-specific AD PRS models and study their relationship with AD and its biomarkers. Methods: We built 13 tissue-specific AD PRS and studied the scores' relationships with AD diagnosis, cerebrospinal fluid (CSF) amyloid, CSF tau, and other CSF biomarkers in two longitudinal cohort studies of AD. Results: The AD PRS model that was most predictive of AD diagnosis (even without APOE) was the liver AD PRS: n = 1,115; odds ratio = 2.15 (1.67-2.78), p = 3.62x10(-9). The liver AD PRS was also statistically significantly associated with cerebrospinal fluid biomarker evidence of amyloid-beta (A beta(42):A beta(40) ratio, p = 3.53x10(-6)) and the phosphorylated tau:amyloid beta ratio (p = 1.45x10(-5)). Conclusion: These findings provide further evidence of the role of the liver-functional genome in AD and the benefits of incorporating functional annotation into genomic research.
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