Margaret Pericak-Vance

University of Miami | UM · John P. Hussman Institute for Human Genomics

Alzheimer’s disease (AD) risk differs between population groups, with African Americans and Hispanics being the most affected groups compared to non-Hispanic Whites. Genetic factors contribute significant risk to AD, but the genetic regulatory architectures (GRA) have primarily been studied in Europeans. Many AD genes are expressed in microglia; th...

One of the core challenges in applying machine learning and artificial intelligence to medicine is the limited availability of annotated medical data. Unlike in other applications of machine learning, where an abundance of labeled data is available, the labeling and annotation of medical data and images require a major effort of manual work by expe...

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study res...

In tandem with the ever‐increasing aging population in low and middle‐income countries, the burden of dementia is rising on the African continent. Dementia prevalence varies from 2.3% to 20.0% and incidence rates are 13.3 per 1000 person‐years with increasing mortality in parts of rapidly transforming Africa. Differences in nutrition, cardiovascula...

Purpose: To clinically and molecularly investigate a new family with North Carolina macular dystrophy (NCMD) from Turkey, a previously unreported geographic origin for this phenotype. Methods: Clinical ophthalmic examinations, including fundus imaging and spectral domain-optical coherence tomography (SD-OCT), were performed on eight members of a...

INTRODUCTION. The difference in APOEϵ4 risk for Alzheimer disease (AD) between different populations is associated with APOEϵ4 local ancestry (LA). We examined LA SNPs with significant frequency differences between African and European/Japanese APOEϵ4 haplotypes for areas of differential regulation. METHODS. We performed two enhancer Massively Para...

Over 90% of variants are rare, and 50% of them are singletons in the Alzheimer's Disease Sequencing Project Whole Exome Sequencing (ADSP WES) data. However, either single variant tests or unit-based tests are limited in the statistical power to detect the association between rare variants and phenotypes. To best utilize rare variants and investigat...

Purpose Common LOXL1 protein-altering variants are significant genetic risk factors for exfoliation syndrome (XFS) and the related secondary glaucoma (XFG). A rare LOXL1 missense allele has been associated with protective effects in a Japanese cohort, suggesting that other rare alleles may also exhibit protective effects. The goal of this study was...

Background: While studying cognition in the Old Order Amish (OOA), we have observed strong performance on the constructional praxis delayed recall (CPDR) as compared to other cognitive tests, independent of overall cognitive status. This may indicate a preferential preservation of visuospatial memory in this population. Here, we investigate this by...

Alzheimer disease (AD) is the most common type of dementia and is currently estimated to affect 6.2 million Americans. It ranks as the sixth leading cause of death in the United States and the proportion of deaths due to AD has been increasing since the year 2000 while the proportion of many other leading causes of deaths have decreased or remained...

Background: Studies of cognitive impairment (CI) in Amish communities have identified sibships containing multiple CI and cognitively unimpaired (CU; unaffected after age 75) individuals. We hypothesize that these CU individuals may carry protective alleles delaying age at onset (AAO) of CI, preserving cognition in older age despite increased genet...

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study res...

Introduction: Findings regarding the association between mitochondrial DNA (mtDNA) variants and Alzheimer's disease (AD) are inconsistent. Methods: We developed a pipeline for accurate assembly and variant calling in mitochondrial genomes embedded within whole exome sequences (WES) from 10,831 participants from the Alzheimer's Disease Sequencing...

Objective Polygenic risk scores (PRSs) assess the individual genetic propensity to a condition by combining sparse information scattered across genetic loci, often displaying small effect sizes. Most PRSs are constructed in European-ancestry populations, limiting their use in other ethnicities. Here we constructed and validated a PRS for late-onset...

INTRODUCTION: The National Institute on Aging Late-Onset Alzheimers Disease Family Based Study (NIA-LOAD FBS) was established to study the genetic etiology of Alzheimers disease (AD). METHODS: Recruitment focused on families with two living affected siblings and a third first degree relative similar in age with or without dementia. Uniform assessme...

The UMi028-A-2 human induced pluripotent stem cell line carries a homozygous mutation (rs377155188, C>G, p.S1038C) in the tetratricopeptide repeat domain 3 (TTC3) gene that was introduced via CRISPR/Cas9 genome editing. The line was originally derived from a neurologically normal male and has been thoroughly characterized following editing. The p.S...

Risk for late-onset Alzheimer's disease (LOAD) is driven by multiple loci primarily identified by genome-wide association studies, many of which are common variants with minor allele frequencies (MAF)>0.01. To identify additional common and rare LOAD risk variants, we performed a GWAS on 25,170 LOAD subjects and 41,052 cognitively normal controls i...

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majori...

Purpose: To evaluate and compare the detection of incomplete and complete retinal pigment epithelial and outer retinal atrophy (iRORA and cRORA) using Spectralis and Cirrus optical coherence tomography (OCT) devices. Methods: Subjects with late age-related macular degeneration (AMD) were imaged on the same day with Spectralis and Cirrus OCT. Two...

Thrombotic storm is a rare clinical entity characterized by acute to subacute thrombosis developing at multiple sites over a few days to a few weeks. An 11-year-old boy presented with headache and facial nerve palsy. He was found to have cortical sinus venous thrombosis and was initiated on low molecular weight heparin, but rapidly progressed with...

Introduction: Apolipoprotein E (APOE) ε4 confers less risk for Alzheimer's disease (AD) in carriers with African local genomic ancestry (ALA) than APOE ε4 carriers with European local ancestry (ELA). Cell type specific transcriptional variation between the two local ancestries (LAs) could contribute to this disease risk differences. Methods: Sin...

The genetic admixture of Caribbean Hispanics provides an opportunity to discover novel genetic factors in Alzheimer disease (AD). We sought to identify genetic variants for AD through a family-based design using the Puerto Rican (PR) Alzheimer Disease Initiative (PRADI). Whole-genome sequencing (WGS) and parametric linkage analysis were performed f...

Background: Lower education has been reported to be associated with dementia. However, many studies have been done in settings where 12 years of formal education is the standard. Formal schooling in the Old Order Amish communities (OOA) ends at 8th grade, which along with their genetic homogeneity, makes it an interesting population to study the e...

Background Most genetic studies on Alzheimer’s disease (AD) have focused on finding risk genes and variants. Taking into account the 30+ loci identified to increase risk of AD, still only around 40‐50% of the estimated heritability of AD is explained. Our goal is to identify genetic variants that delay the onset or protect against the development o...

Background Addressing the disparity Late Onset Alzheimer’s disease (LOAD) prevalence among African Americans (AA) requires deliberate inclusion of this population in Alzheimer’s disease (AD) studies. Recruiting AA for research studies remains a significant challenge for AD genetic studies. Recruiting and retaining AA males (AAMs) is an even greater...

Background Recent meta‐analyses of genome‐wide association studies (GWAS) have identified ∼30 susceptibility LOAD loci in addition to APOE , however the majority are common variants (minor allele frequency (MAF)>0.02). We used the dense, high‐resolution Haplotype Reference Consortium (HRC) r1.1 reference panel (64,976 haplotypes/39,235,157 SNPs), w...

Background There is limited study of the effect of genetically determined ancestral background and diabetic risk on cognitive status in admixed populations. Puerto Ricans are an admixed population with European (EU), African (AF), and Amerindian (AI) backgrounds. We analyzed the impact of ancestry and diabetes on cognitive status in older Puerto Ri...

Background Genetic risk factors for Alzheimer disease (AD) demonstrate distinct effects across diverse ancestral populations. The ancestral heterogeneity (admixture) of Caribbean Hispanics from Puerto Rico (PR), makes studies of the PR population important in the discovery of ancestry‐specific factors in AD. To expand ongoing genomic investigations...

Background The APOE ε4 allele is a major risk factor for AD whose effect shows strong racial/ethnic differences. Among non‐Hispanic White (NHW) populations APOE shows the strongest effect in Northern European (NEu) (rs429358: OR = 3.32, CI:3.20‐3.45) and has a relatively lower effect in Southern European (SEu; i.e., Iberia, Italy, etc) populations...

Background Recent reports suggest that the rare APOE Christchurch mutation and APOE2 allele protect against Alzheimer’s disease (AD) pathology by reducing the burden of tau pathology. However, the mechanism(s) underlying the APOE2 protective effect linking to tau is largely unknown. Method We conducted a genome‐wide association study (GWAS) for AD...

Background Genetic studies in Alzheimer disease (AD) are underrepresented in African‐descent populations. The African American (AA),population, with the admixed genetic ancestry (African and European) and high African ancestral background (∼80%), provides a unique opportunity to discover African ancestry‐specific genetic factors in AD. Admixture ma...

Background Most significant genome‐wide association markers for Alzheimer disease (AD) are in noncoding portions of the genome making assigning a corresponding gene involved in risk challenging. Coding variants identified in some these GWAS loci thus far do not explain the proportion of risk attributable to the associated markers, indicating a cont...

Background The ApoEε4 allele is a major risk factor for AD whose effect shows strong racial/ethnic differences. Among the populations ApoE shows the strongest effect in East Asians (EA) (ε3/ε4 odds ratio OR: 3.1–5.6; ε4/ε4 OR: 11.8–33.1) and has a relatively lower effect in non‐Hispanic Whites (NHW) (ε3/ε4 OR: 3.2; ε4/ε4 OR: 14.9). The effect of Ap...

Background The ATP‐binding cassette, sub‐family A (ABC1), member 7 ( ABCA7 ) gene has been implicated as a risk factor in Alzheimer’s disease (AD) across populations. However, the risk effect of ABCA7 in African Americans (AAs) is stronger than in non‐Hispanic white (NHW) populations. We identified a 44 base pair deletion in AA significantly associ...

Background The risk for late‐onset Alzheimer disease (AD) in ApoEε4 carriers differs between ancestral groups. ApoEε4 Non‐Hispanic White (NHW) homozygotes have an odds ratio of 14.9 while the risk is much lower in Africans (AF) (OR 2.2‐5.7). Local ancestry (LA) analyses in ApoEε4 carrier populations have shown the protective effect in Africans rela...

Background With over 5.1 million individuals, the Puerto Rican population makes up over 1.5% of the US population and is the 2nd largest Hispanic/Latino population in the continental US. There are an estimated of 60,000 cases of AD on the island. The Puerto Rico Alzheimer's and Related Dementias Initiatives (PRADI) cohort will both leverage and com...

Background The ADSP‐FUS is a National Institute on Aging (NIA) initiative focused on identifying genetic risk and protective variants for late‐onset Alzheimer Disease (LOAD). A major concern in AD genetic studies is a lack of racial‐ethnic diversity. The ADSP‐FUS collects and sequences existing both ethnically diverse and unique cohorts with extens...

Background Over 20 genetic loci have been consistently associated with Alzheimer disease (AD) with accumulating evidence pointing to alterations of the endolysosomal pathway as playing key roles. The sortilin‐related receptor 1 ( SORL1 ) gene has been associated with AD through multiple genetic studies and has been suggested to function by guiding...

Background Genome‐wide association studies (GWAS) have identified approximately 40 risk loci associated with Alzheimer’s disease (AD). However, only a fraction of heritability has been explained. In large meta‐analysis, smoking was associated with AD dementia. In this study, we sought to identify interactions between smoking and single‐nucleotide p...

Background The Alzheimer’s Disease Sequencing Project (ADSP) seeks to identify genomic variants contributing to increased risk of and/or protection from Alzheimer’s disease (AD) in multi‐ethnic populations. Here we report on statistical modeling considerations and results from 4707 diverse individuals including 2076 non‐Hispanic White, 1030 Black,...

Background APOEε4 is the strongest genetic risk factor for Alzheimer Disease (AD) in European populations. African local genomic ancestry (LA) surrounding the APOEε4 allele has been associated with a decreased risk for AD in African‐American (AA) carriers relative to European LA in Non‐Hispanic Whites (NHW) (Rajalbi et al 2018). Identifying the cau...

Background Increased years of education have been previously associated with a decreased risk of developing Alzheimer disease (AD) with cognitive reserve suggested as the source of the protective effect in Non‐Hispanic Whites (NHW). African Americans (AA) are twice as likely to develop AD compared to NHW. We investigated the hypothesis that educati...

Background Late‐onset Alzheimer’s disease (AD) is a complex disorder with multiple genetic risk factors. Linkage and association analysis have mapped dozens of loci in pooled analysis of many pedigrees or large numbers of unrelated cases and controls. Identification of the underlying DNA risk variants in the regions of interest (ROIs) has been comp...

Background The Modified Mini‐Mental State (3MS) is a widely used measure of global cognition. The Old Order Amish are both genetically and environmentally homogeneous, with similar years of formal education across the population. Here, we investigated the longitudinal course of cognitive function as measured by the distribution of 3MS in the Mid‐We...

Background Recent work suggests unexplained heritability of Alzheimer’s Disease (AD) may involve rare variants in genes implicated in other neurodegenerative disorders. However, existing gene‐based tests have insufficient power to detect true associations when neutral variants are included. Therefore, identifying variants with potentially high impa...

Background Alzheimer’s disease (AD) has become a burden of social and economic importance, affecting millions of families and society at large. The Puerto Rico Alzheimer and Related Dementias Initiatives (PRADI) cohort was developed to investigate AD and genetics factors of AD in the Puerto Rican population. PRADI recruitment was a snowball samplin...

Background Most studies on Alzheimer Disease (AD) have focused on the identification of variants associated with increased risk. The Amish is a genetically homogeneous population ideal to investigate susceptibility genes for complex traits such as AD. This study aims to use family‐based linkage and association approaches to identify genetic variant...

Background Understanding the effects of genetic factors that drive Alzheimer’s Disease (AD) pathogenesis, including genetic differences across diverse ancestral populations, will drive discovery of novel pharmacological targets. Weighted gene co‐expression network analysis (WGCNA) is a powerful method for finding gene clusters (modules) with correl...

Background Studies have shown that the lower risk associated with the ε4 allele for African ancestry is associated with the local ancestry (LA) surrounding the ApoE gene. Previous studies have shown differences between ApoE3 and ApoE4 alleles in isogenic induced pluripotent stem cell (iPSC) models when exposed to Aβ. We hypothesized that ApoE4 indi...

Background Using sequencing from multi‐ethnic AD studies, the ADSP aims to identify genomic variation contributing to elevated risk of, or protection from, AD. We examined coding region variation in the ADSP WES (whole exome sequencing) Release 2 dataset, comprising jointly‐called genotypes on 12,135 non‐Hispanic White (NHW), 4,108 African American...

Background To identify LOAD risk genes in Puerto Ricans (PR), a population underrepresented in genetic studies, linkage analysis of whole genome sequencing (WGS) in 23 multiplex PR families identified a peak on chromosome 9p21 (MLOD = 3.9). The 1‐LOD unit down region spans from 31∼38Mb; identity‐by‐descent (IBD) sharing region spans from 23‐39 Mb....

Alzheimer disease (AD) is the leading cause of dementia in the elderly and occurs in all ethnic and racial groups. The apolipoprotein E (ApoE) ε4 is the most significant genetic risk factor for late-onset AD and shows the strongest effect among East Asian populations followed by non-Hispanic White (NHW) populations and has a relatively lower effect...

Background Recent reports suggest that the rare apolipoprotein E ( APOE ) Christchurch mutation and ε2 allele protect against Alzheimer’s disease (AD) pathology by reducing the burden of tau pathology. However, the mechanism(s) underlying the ε2 protective effect linking to tau is largely unknown. Methods The role of the ε2 allele in Alzheimer’s d...

Background: The Latino population is greatly understudied in biomedical research, including genetics. Very little information is available on presence of known variants originally identified in non-Hispanic white patients or novel variants in the Latino population. The Latino population is admixed, with contributions of European, African, and Ameri...

Although an optical coherence tomography (OCT)-derived central drusen volume ≥0.03 mm³ has been found to be a risk factor for progression to late age-related macular degeneration (AMD), this parameter is not currently available on most OCT devices or acquisition protocols. The purpose of this study was to evaluate the ability of human graders to qu...

Importance Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association...

Deciphering the genetic landscape of Alzheimer’s disease (AD) is essential to define the pathophysiological pathways involved and to successfully translate genomics to potential tailored medical care. To generate the most complete knowledge of the AD genetics, we developed through the European Alzheimer’s Disease BioBank (EADB) consortium a discove...

Autism features occur frequently among individuals with eating disorders (ED). This co‐occurrence is not well understood but there is speculation that select traits (e.g., rigidity) are common to both autism and ED. To explore the co‐occurrence of autistic traits and ED features, we used the Simons Simplex Collection (SSC; N = 2,623 families) to te...

Background: Identifying and understanding the functional role of genetic risk factors for Alzheimer disease (AD) has been complicated by the variability of genetic influences across brain regions and confounding with age-related neurodegeneration. Methods: A gene co-expression network was constructed using data obtained from the Allen Brain Atla...

The Alzheimer's Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to sel...

A correction to this paper has been published and can be accessed via a link at the top of the paper.

Approximately 30% of older adults exhibit the neuropathological features of Alzheimer's disease without signs of cognitive impairment. Yet, little is known about the genetic factors that allow these potentially resilient individuals to remain cognitively unimpaired in the face of substantial neuropathology. We performed a large, genome-wide associa...

There is limited study of the effect of genetically determined ancestral background and diabetic risk on cognitive status in admixed populations. Puerto Ricans are an admixed population with European (EU), African (AF), and Amerindian (AI) backgrounds. We analyzed the impact of ancestry and diabetes on cognitive status in older Puerto Ricans.

The genetic component of Alzheimers disease (AD) has been mainly assessed using Genome Wide Association Studies (GWAS), which do not capture the risk contributed by rare variants. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals —16,036 AD cases and 16,522 controls— in a two-stage an...

Background: Significant work has identified genetic variants conferring risk and protection for Alzheimer's disease (AD), but functional effects of these variants is lacking, particularly in under-represented ancestral populations. Expression studies performed in easily accessible tissue, such as whole blood, can recapitulate some transcriptional...

From its inception in 1980, advancement of research was one of the primary missions of the Alzheimer's Association (also known as Alzheimer's Disease and Related Disorders Association) in addition to leading in family caregiver support, better care, public education, and awareness. Over the past 30 years, the Association has grown and expanded its...

Objective Here, we re-examine TOMM40 -523′ as a race/ethnicity-specific risk modifier for late-onset Alzheimer disease (LOAD) with adjustment for local genomic ancestry (LGA) in Apolipoprotein E ( APOE) ε 4 haplotypes. Methods The TOMM40 -523′ size was determined by fragment analysis and whole genome sequencing in homozygous APOE ε 3 and APOE ε 4...

APOEϵ4 African local genomic ancestry (LA) confers less risk for Alzheimer disease (AD) relative to European LA (LA) carriers. Single nucleus RNA sequencing from AD-APOEϵ4/4 frontal cortex found European LA carriers have a 1.45-fold greater APOEϵ4 expression (p< 1.8 E10-313) and are associated with a unique A1 reactive astrocyte cluster. This sugge...

Background The ancestral genetic heterogeneity (admixture) of Caribbean Hispanics makes studies of this population critical to the discovery of ancestry-specific genetic factors in Alzheimer disease. In this study, we performed whole genome sequencing in multiplex Caribbean Hispanic Puerto Rican families to identify rare causal variants influencing...

Alzheimer disease (AD) is the leading cause of dementia in the elderly and occurs in all ethnic and racial groups. ApoE ε4 is the most significant genetic risk factor for late-onset AD and shows the strongest effect among East Asian populations followed by non-Hispanic White populations and has a relatively lower effect in African descent populatio...

Approximately 30% of older adults exhibit the neuropathologic features of Alzheimer's disease (AD) without signs of cognitive impairment. Yet, little is known about the genetic factors that allow these potentially resilient individuals to remain cognitively normal in the face of substantial neuropathology. We performed a large, genome-wide associat...

Whole exome sequencing and copy‐number variant analysis was performed on a family with three brothers diagnosed with autism. Each of the siblings shares an alteration in the nuclear receptor subfamily 3 group C member 2 (NR3C2) gene that is predicted to result in a stop‐gain mutation (p.Q919X) in the mineralocorticoid receptor (MR) protein. This va...

Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer’s dementia, while the APOE2 allele is associated with a lower risk of Alzheimer’s dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer’s dementia odds ratios and other findings in more th...

Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer's dementia, while the APOE2 allele is associated with a lower risk of Alzheimer's dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer's dementia odds ratios and other findings in more th...

We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptiv...

Genome-wide association studies (GWAS) have identified more than 50,000 unique associations with common human traits. While this represents a substantial step forward, establishing the biology underlying these associations has proven extremely difficult. Even determining which cell types and which particular gene(s) are relevant continues to be a c...