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Article ; Online: Correlation-based tests for the formal comparison of polygenic scores in multiple populations.

Gunn, Sophia / Lunetta, Kathryn L

2024 Volume 20, Issue 4, Page(s) e1011249

Abstract: Polygenic scores (PGS) are measures of genetic risk, derived from the results of genome wide association studies (GWAS). Previous work has proposed the coefficient of determination (R2) as an appropriate measure by which to compare PGS performance in a ... ...

Abstract	Polygenic scores (PGS) are measures of genetic risk, derived from the results of genome wide association studies (GWAS). Previous work has proposed the coefficient of determination (R2) as an appropriate measure by which to compare PGS performance in a validation dataset. Here we propose correlation-based methods for evaluating PGS performance by adapting previous work which produced a statistical framework and robust test statistics for the comparison of multiple correlation measures in multiple populations. This flexible framework can be extended to a wider variety of hypothesis tests than currently available methods. We assess our proposed method in simulation and demonstrate its utility with two examples, assessing previously developed PGS for low-density lipoprotein cholesterol and height in multiple populations in the All of Us cohort. Finally, we provide an R package 'coranova' with both parametric and nonparametric implementations of the described methods.
Language	English
Publishing date	2024-04-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1011249
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Article ; Online: Addition of polygenic risk score to a risk calculator for prediction of breast cancer in US Black women.

Zirpoli, Gary R / Pfeiffer, Ruth M / Bertrand, Kimberly A / Huo, Dezheng / Lunetta, Kathryn L / Palmer, Julie R

Breast cancer research : BCR

2024 Volume 26, Issue 1, Page(s) 2

Abstract: Background: Previous work in European ancestry populations has shown that adding a polygenic risk score (PRS) to breast cancer risk prediction models based on epidemiologic factors results in better discriminatory performance as measured by the AUC ( ... ...

Abstract	Background: Previous work in European ancestry populations has shown that adding a polygenic risk score (PRS) to breast cancer risk prediction models based on epidemiologic factors results in better discriminatory performance as measured by the AUC (area under the curve). Following publication of the first PRS to perform well in women of African ancestry (AA-PRS), we conducted an external validation of the AA-PRS and then evaluated the addition of the AA-PRS to a risk calculator for incident breast cancer in Black women based on epidemiologic factors (BWHS model). Methods: Data from the Black Women's Health Study, an ongoing prospective cohort study of 59,000 US Black women followed by biennial questionnaire since 1995, were used to calculate AUCs and 95% confidence intervals (CIs) for discriminatory accuracy of the BWHS model, the AA-PRS alone, and a new model that combined them. Analyses were based on data from 922 women with invasive breast cancer and 1844 age-matched controls. Results: AUCs were 0.577 (95% CI 0.556-0.598) for the BWHS model and 0.584 (95% CI 0.563-0.605) for the AA-PRS. For a model that combined estimates from the questionnaire-based BWHS model with the PRS, the AUC increased to 0.623 (95% CI 0.603-0.644). Conclusions: This combined model represents a step forward for personalized breast cancer preventive care for US Black women, as its performance metrics are similar to those from models in other populations. Use of this new model may mitigate exacerbation of breast cancer disparities if and when it becomes feasible to include a PRS in routine health care decision-making.
MeSH term(s)	Female ; Humans ; Breast Neoplasms/diagnosis ; Breast Neoplasms/epidemiology ; Breast Neoplasms/genetics ; Genetic Predisposition to Disease ; Genetic Risk Score ; Polymorphism, Single Nucleotide ; Prospective Studies ; Risk Assessment ; Risk Factors ; Black or African American
Language	English
Publishing date	2024-01-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2015059-3
ISSN	1465-542X ; 1465-5411
ISSN (online)	1465-542X
ISSN	1465-5411
DOI	10.1186/s13058-023-01748-8
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Article ; Online: Methods for meta-analysis of genetic data.

Lunetta, Kathryn L

Current protocols in human genetics

2013 Volume Chapter 1, Page(s) Unit1.24

Abstract: Modern genetic association studies, using genome-wide genotype data, are often underpowered. Meta-analyses of multiple studies performing genome-wide genotyping improve power and have led to the identification of thousands of genotype-trait associations. ...

Abstract	Modern genetic association studies, using genome-wide genotype data, are often underpowered. Meta-analyses of multiple studies performing genome-wide genotyping improve power and have led to the identification of thousands of genotype-trait associations. This unit provides an overview of the key concepts required for genetic meta-analyses, and presents strategic approaches and key decisions that must be made in the process of performing genome-wide association study (GWAS) meta-analyses. The commentary discusses the interpretation of GWAS meta-analysis results, complications, and some of the possible next steps once a GWAS meta-analysis has successfully identified regions associated with a trait.
MeSH term(s)	Databases, Genetic ; Genetic Association Studies/methods ; Genotype ; Humans ; Meta-Analysis as Topic ; Microarray Analysis/methods ; Models, Theoretical ; Phenotype ; Polymorphism, Single Nucleotide ; Software
Language	English
Publishing date	2013
Publishing country	United States
Document type	Journal Article
ISSN	1934-8258
ISSN (online)	1934-8258
DOI	10.1002/0471142905.hg0124s77
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Article: Aging-Related Immune Cell Phenotypes and Mortality in the Framingham Heart Study.

Ragab, Ahmed A Y / Doyle, Margaret F / Chen, Jiachen / Fang, Yuan / Lunetta, Kathryn L / Murabito, Joanne M

Research square

2023

Abstract: Background: The global increase in human life expectancy is evident. The total number of individuals aged 60 or above is anticipated to reach 2 billion by 2050. Aging, an inherently complex process, manifests prominently in the changes observed in the ... ...

Abstract	Background: The global increase in human life expectancy is evident. The total number of individuals aged 60 or above is anticipated to reach 2 billion by 2050. Aging, an inherently complex process, manifests prominently in the changes observed in the immune system. A notable marker of immune system aging is the presence of Aging-Related Immune Cell Phenotypes (ARIPs). Despite their significance, the connections between various ARIPs and mortality have not been thoroughly investigated. We prospectively investigated 16 different ARIPs using flow cytometry, namely, CD4/CD8 ratio, Granzyme B + CD8/Granyzme B + CD4, T Results: Among 996 participants (mean age 62 years, range 40 to 88 years, 52% female), the survival rate was 65% during 19 years of follow-up. For the model adjusting for age, sex, and cytomegalovirus (CMV) serostatus, higher CD4/CD8 and Tc17/CD8 + Treg ratios were significantly associated with lower all-cause mortality (HR:0.86 [0.76-0.96], 0.84 [0.74-0.94], respectively) and higher CD8 regulatory cell levels (CD8 + CD25 + FoxP3+) were associated with higher all-cause mortality (HR = 1.17, [1.03-1.32]). Higher IL-6 levels were associated with higher all-cause, cardiovascular, and non-cardiovascular mortality (HR = 1.43 [1.26-1.62], 1.70 [1.31-2.21], and 1.36 [1.18-1.57], respectively).
Language	English
Publishing date	2023-12-26
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3773986/v1
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Article ; Online: Adjusting for common variant polygenic scores improves yield in rare variant association analyses.

Jurgens, Sean J / Pirruccello, James P / Choi, Seung Hoan / Morrill, Valerie N / Chaffin, Mark / Lubitz, Steven A / Lunetta, Kathryn L / Ellinor, Patrick T

Nature genetics

2023 Volume 55, Issue 4, Page(s) 544–548

Abstract: With the emergence of large-scale sequencing data, methods for improving power in rare variant association tests are needed. Here we show that adjusting for common variant polygenic scores improves yield in gene-based rare variant association tests ... ...

Abstract	With the emergence of large-scale sequencing data, methods for improving power in rare variant association tests are needed. Here we show that adjusting for common variant polygenic scores improves yield in gene-based rare variant association tests across 65 quantitative traits in the UK Biobank (up to 20% increase at α = 2.6 × 10
MeSH term(s)	Multifactorial Inheritance/genetics ; Phenotype ; Quantitative Trait Loci ; Polymorphism, Single Nucleotide/genetics ; Models, Genetic ; Genome-Wide Association Study
Language	English
Publishing date	2023-03-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1108734-1
ISSN	1546-1718 ; 1061-4036
ISSN (online)	1546-1718
ISSN	1061-4036
DOI	10.1038/s41588-023-01342-w
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Zs.A 3613: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: A novel principal component based method for identifying differentially methylated regions in Illumina Infinium MethylationEPIC BeadChip data.

Zheng, Yuanchao / Lunetta, Kathryn L / Liu, Chunyu / Smith, Alicia K / Sherva, Richard / Miller, Mark W / Logue, Mark W

Epigenetics

2023 Volume 18, Issue 1, Page(s) 2207959

Abstract: Differentially methylated regions (DMRs) are genomic regions with methylation patterns across multiple CpG sites that are associated with a phenotype. In this study, we proposed a Principal Component (PC) based DMR analysis method for use with data ... ...

Abstract	Differentially methylated regions (DMRs) are genomic regions with methylation patterns across multiple CpG sites that are associated with a phenotype. In this study, we proposed a Principal Component (PC) based DMR analysis method for use with data generated using the Illumina Infinium MethylationEPIC BeadChip (EPIC) array. We obtained methylation residuals by regressing the M-values of CpGs within a region on covariates, extracted PCs of the residuals, and then combined association information across PCs to obtain regional significance. Simulation-based genome-wide false positive (GFP) rates and true positive rates were estimated under a variety of conditions before determining the final version of our method, which we have named DMR
MeSH term(s)	Epigenesis, Genetic ; DNA Methylation ; Epigenome ; Phenotype ; Smoking ; CpG Islands ; Genome-Wide Association Study
Language	English
Publishing date	2023-05-13
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ISSN	1559-2308
ISSN (online)	1559-2308
DOI	10.1080/15592294.2023.2207959
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Article ; Online: APOE genotype-specific methylation patterns are linked to Alzheimer disease pathology and estrogen response.

Panitch, Rebecca / Sahelijo, Nathan / Hu, Junming / Nho, Kwangsik / Bennett, David A / Lunetta, Kathryn L / Au, Rhoda / Stein, Thor D / Farrer, Lindsay A / Jun, Gyungah R

Translational psychiatry

2024 Volume 14, Issue 1, Page(s) 129

Abstract: The joint effects of APOE genotype and DNA methylation on Alzheimer disease (AD) risk is relatively unknown. We conducted genome-wide methylation analyses using 2,021 samples in blood (91 AD cases, 329 mild cognitive impairment, 1,391 controls) and 697 ... ...

Abstract	The joint effects of APOE genotype and DNA methylation on Alzheimer disease (AD) risk is relatively unknown. We conducted genome-wide methylation analyses using 2,021 samples in blood (91 AD cases, 329 mild cognitive impairment, 1,391 controls) and 697 samples in brain (417 AD cases, 280 controls). We identified differentially methylated levels in AD compared to controls in an APOE genotype-specific manner at 25 cytosine-phosphate-guanine (CpG) sites in brain and 36 CpG sites in blood. Additionally, we identified seven CpG sites in the APOE region containing TOMM40, APOE, and APOC1 genes with P < 5 × 10
MeSH term(s)	Humans ; Alzheimer Disease/metabolism ; Apolipoprotein E4/genetics ; Apolipoproteins E/genetics ; DNA Methylation ; Estrogens ; Genotype
Chemical Substances	Apolipoprotein E4 ; Apolipoproteins E ; Estrogens ; ApoE protein, human
Language	English
Publishing date	2024-02-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	2609311-X
ISSN	2158-3188 ; 2158-3188
ISSN (online)	2158-3188
ISSN	2158-3188
DOI	10.1038/s41398-024-02834-x
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Article ; Online: Set-Based Rare Variant Expression Quantitative Trait Loci in Blood and Brain from Alzheimer Disease Study Participants.

Patel, Devanshi / Zhang, Xiaoling / Farrell, John J / Lunetta, Kathryn L / Farrer, Lindsay A

Genes

2021 Volume 12, Issue 3

Abstract: Because studies of rare variant effects on gene expression have limited power, we investigated set-based methods to identify rare expression quantitative trait loci (eQTL) related to Alzheimer disease (AD). Gene-level and pathway-level cis rare-eQTL ... ...

Abstract	Because studies of rare variant effects on gene expression have limited power, we investigated set-based methods to identify rare expression quantitative trait loci (eQTL) related to Alzheimer disease (AD). Gene-level and pathway-level cis rare-eQTL mapping was performed genome-wide using gene expression data derived from blood donated by 713 Alzheimer's Disease Neuroimaging Initiative participants and from brain tissues donated by 475 Religious Orders Study/Memory and Aging Project participants. The association of gene or pathway expression with a set of all cis potentially regulatory low-frequency and rare variants within 1 Mb of genes was evaluated using SKAT-O. A total of 65 genes expressed in the brain were significant targets for rare expression single nucleotide polymorphisms (eSNPs) among which 17% (11/65) included established AD genes
MeSH term(s)	Aged ; Aged, 80 and over ; Alzheimer Disease/genetics ; Brain/pathology ; Female ; Gene Expression/genetics ; Gene Expression Regulation/genetics ; Genetic Predisposition to Disease/genetics ; Genome-Wide Association Study/methods ; Humans ; Immune System/physiology ; Inflammation/genetics ; Male ; Polymorphism, Single Nucleotide/genetics ; Quantitative Trait Loci/genetics ; Signal Transduction/genetics
Language	English
Publishing date	2021-03-15
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes12030419
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Article ; Online: An evaluation of the genome-wide false positive rates of common methods for identifying differentially methylated regions using illumina methylation arrays.

Zheng, Yuanchao / Lunetta, Kathryn L / Liu, Chunyu / Katrinli, Seyma / Smith, Alicia K / Miller, Mark W / Logue, Mark W

Epigenetics

2022 Volume 17, Issue 13, Page(s) 2241–2258

Abstract: Differentially methylated regions (DMRs) are genomic regions with specific methylation patterns across multiple loci that are associated with a phenotype. We examined the genome-wide false positive (GFP) rates of five widely used DMR methods: comb-p, ... ...

Abstract	Differentially methylated regions (DMRs) are genomic regions with specific methylation patterns across multiple loci that are associated with a phenotype. We examined the genome-wide false positive (GFP) rates of five widely used DMR methods: comb-p, Bumphunter, DMRcate, mCSEA and coMethDMR using both Illumina HumanMethylation450 (450 K) and MethylationEPIC (EPIC) data and simulated continuous and dichotomous null phenotypes (i.e., generated independently of methylation data). coMethDMR provided well-controlled GFP rates (~5%) except when analysing skewed continuous phenotypes. DMRcate generally had well-controlled GFP rates when applied to 450 K data except for the skewed continuous phenotype and EPIC data only for the normally distributed continuous phenotype. GFP rates for mCSEA were at least 0.096 and comb-p yielded GFP rates above 0.34. Bumphunter had high GFP rates of at least 0.35 across conditions, reaching as high as 0.95. Analysis of the performance of these methods in specific regions of the genome found that regions with higher correlation across loci had higher regional false positive rates on average across methods. Based on the false positive rates, coMethDMR is the most recommended analysis method, and DMRcate had acceptable performance when analysing 450 K data. However, as both could display higher levels of FPs for skewed continuous distributions, a normalizing transformation of skewed continuous phenotypes is suggested. This study highlights the importance of genome-wide simulations when evaluating the performance of DMR-analysis methods.
MeSH term(s)	CpG Islands ; DNA Methylation ; Genome ; High-Throughput Nucleotide Sequencing ; Genomics/methods
Language	English
Publishing date	2022-09-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1559-2308
ISSN (online)	1559-2308
DOI	10.1080/15592294.2022.2115600
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Article ; Online: Cross-Sectional Association Between Blood Cell Phenotypes, Cognitive Function, and Brain Imaging Measures in the Community-Based Framingham Heart Study.

Fang, Yuan / Doyle, Margaret F / Alosco, Michael L / Mez, Jesse / Satizabal, Claudia L / Qiu, Wei Qiao / Lunetta, Kathryn L / Murabito, Joanne M

Journal of Alzheimer's disease : JAD

2022 Volume 87, Issue 3, Page(s) 1291–1305

Abstract: Background: Peripheral inflammation is associated with increased risk for dementia. Neutrophil to lymphocyte ratio (NLR), red cell distribution width (RDW), and mean platelet volume (MPV), are easily measured circulating blood cell phenotypes reflecting ...

Abstract	Background: Peripheral inflammation is associated with increased risk for dementia. Neutrophil to lymphocyte ratio (NLR), red cell distribution width (RDW), and mean platelet volume (MPV), are easily measured circulating blood cell phenotypes reflecting chronic peripheral inflammation, but their association with dementia status is unclear. Objective: We sought to investigate the cross-sectional association of these inflammatory measures with neuropsychological (NP) test performance, and brain magnetic resonance imaging (MRI) measures in the Framingham Heart Study (FHS) Offspring, Third-generation, and Omni cohorts. Methods: We identified FHS participants who attended an exam that included a complete blood cell count (CBC) and underwent NP testing (n = 3,396) or brain MRI (n = 2,770) within five years of blood draw. We investigated the association between NLR, RDW, and MPV and NP test performance and structural MRI-derived volumetric measurements using linear mixed effect models accounting for family relationships and adjusting for potential confounders. Results: Participants were on average 60 years old, 53% female, and about 80% attended some college. Higher NLR was significantly associated with poorer performance on visual memory, and visuospatial abilities, as well as with larger white matter hyperintensity volume. We also observed associations for higher RDW with poorer executive function and smaller total cerebral brain volume. Conclusion: Chronic peripheral inflammation as measured by NLR and RDW was associated with worse cognitive function, reduced brain volume, and greater microvascular disease in FHS participants. If confirmed in other samples, CBC may provide informative and cost-effective biomarkers of abnormal brain aging in the community.
MeSH term(s)	Brain/diagnostic imaging ; Brain/pathology ; Cognition ; Cross-Sectional Studies ; Dementia/pathology ; Female ; Humans ; Inflammation/pathology ; Longitudinal Studies ; Lymphocytes ; Male ; Neuroimaging ; Phenotype
Language	English
Publishing date	2022-04-11
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-215533
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