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- Coignard, J, et al.
(författare)
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A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers
- 2021
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 1078-
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.
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- Dareng, EO, et al.
(författare)
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Polygenic risk modeling for prediction of epithelial ovarian cancer risk
- 2022
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Ingår i: European journal of human genetics : EJHG. - : Springer Science and Business Media LLC. - 1476-5438 .- 1018-4813. ; 30:3, s. 349-362
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Tidskriftsartikel (refereegranskat)abstract
- Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, “select and shrink for summary statistics” (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28–1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08–1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21–1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29–1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35–1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
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- Cousins, Katheryn A Q, et al.
(författare)
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ATN incorporating cerebrospinal fluid neurofilament light chain detects frontotemporal lobar degeneration.
- 2021
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 17:5, s. 822-830
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Tidskriftsartikel (refereegranskat)abstract
- The ATN framework provides an in vivo diagnosis of Alzheimer's disease (AD) using cerebrospinal fluid (CSF) biomarkers of pathologic amyloid plaques (A), tangles (T), and neurodegeneration (N). ATN is rarely evaluated in pathologically confirmed patients and its poor sensitivity to suspected non-Alzheimer's pathophysiologies (SNAP), including frontotemporal lobar degeneration (FTLD), leads to misdiagnoses. We compared accuracy of ATN (ATNTAU ) using CSF total tau (t-tau) to a modified strategy (ATNNfL ) using CSF neurofilament light chain (NfL) in an autopsy cohort.ATNTAU and ATNNfL were trained in an independent sample and validated in autopsy-confirmed AD (n = 67) and FTLD (n = 27).ATNNfL more accurately identified FTLD as SNAP (sensitivity = 0.93, specificity = 0.94) than ATNTAU (sensitivity = 0.44, specificity = 0.97), even in cases with co-occurring AD and FTLD. ATNNfL misclassified fewer AD and FTLD as "Normal" (2%) than ATNTAU (14%).ATNNfL is a promising diagnostic strategy that may accurately identify both AD and FTLD, even when pathologies co-occur.
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- Zuroff, Leah, et al.
(författare)
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Self- and Partner-Reported Subjective Memory Complaints : Association with Objective Cognitive Impairment and Risk of Decline
- 2022
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Ingår i: Journal of Alzheimer's Disease Reports. - 2542-4823. ; 6:1, s. 411-430
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Tidskriftsartikel (refereegranskat)abstract
- Background: Episodic memory decline is a hallmark of Alzheimer's disease (AD). Subjective memory complaints (SMCs) may represent one of the earliest signs of impending cognitive decline. The degree to which self- or partner-reported SMCs predict cognitive change remains unclear. Objective: We aimed to evaluate the relationship between self- and partner-reported SMCs, objective cognitive performance, AD biomarkers, and risk of future decline in a well-characterized longitudinal memory center cohort. We also evaluated whether study partner characteristics influence reports of SMCs. Methods: 758 participants and 690 study partners were recruited from the Penn Alzheimer's Disease Research Center Clinical Core. Participants included those with Normal Cognition, Mild Cognitive Impairment, and AD. SMCs were measured using the Prospective and Retrospective Memory Questionnaire (PRMQ), and were evaluated for their association with cognition, genetic, plasma, and neuroimaging biomarkers of AD, cognitive and functional decline, and diagnostic progression over an average of four years. Results: We found that partner-reported SMCs were more consistent with cognitive test performance and increasing symptom severity than self-reported SMCs. Partner-reported SMCs showed stronger correlations with AD-associated brain atrophy, plasma biomarkers of neurodegeneration, and longitudinal cognitive and functional decline. A 10-point increase on baseline PRMQ increased the annual risk of diagnostic progression by approximately 70%. Study partner demographics and relationship to participants influenced reports of SMCs in AD participants only. Conclusion: Partner-reported SMCs, using the PRMQ, have a stronger relationship with the neuroanatomic and cognitive changes associated with AD than patient-reported SMCs. Further work is needed to evaluate whether SMCs could be used to screen for future decline.
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