Publications by authors named "Badri N Vardarajan"

42 Publications

Linkage of Alzheimer disease families with Puerto Rican ancestry identifies a chromosome 9 locus.

Neurobiol Aging 2021 Aug 28;104:115.e1-115.e7. Epub 2021 Feb 28.

John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA; Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA.

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 for 100 individuals from 23 multiplex PRADI families. Variants were prioritized by minor allele frequency (<0.01), functional potential [combined annotation dependent depletion score (CADD) >10], and co-segregation with AD. Variants were further ranked using an independent PR case-control WGS dataset (PR10/66). A genome-wide significant linkage peak was found in 9p21 with a heterogeneity logarithm of the odds score (HLOD) >5.1, which overlaps with an AD linkage region from two published independent studies. The region harbors C9orf72, but no expanded repeats were observed in the families. Seven variants prioritized by the PRADI families also displayed evidence for association in the PR10/66 (p < 0.05), including a missense variant in UNC13B. Our study demonstrated the importance of family-based design and WGS in genetic study of AD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.02.019DOI Listing
August 2021

A quantitative trait rare variant nonparametric linkage method with application to age-at-onset of Alzheimer's disease.

Eur J Hum Genet 2020 12 1;28(12):1734-1742. Epub 2020 Aug 1.

Center for Statistical Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.

To analyze pedigrees with quantitative trait (QT) and sequence data, we developed a rare variant (RV) quantitative nonparametric linkage (QNPL) method, which evaluates sharing of minor alleles. RV-QNPL has greater power than the traditional QNPL that tests for excess sharing of minor and major alleles. RV-QNPL is robust to population substructure and admixture, locus heterogeneity, and inclusion of nonpathogenic variants and can be readily applied outside of coding regions. When QNPL was used to analyze common variants, it often led to loci mapping to large intervals, e.g., >40 Mb. In contrast, when RVs are analyzed, regions are well defined, e.g., a gene. Using simulation studies, we demonstrate that RV-QNPL is substantially more powerful than applying traditional QNPL methods to analyze RVs. RV-QNPL was also applied to analyze age-at-onset (AAO) data for 107 late-onset Alzheimer's disease (LOAD) pedigrees of Caribbean Hispanic and European ancestry with whole-genome sequence data. When AAO of AD was analyzed regardless of APOE ε4 status, suggestive linkage (LOD = 2.4) was observed with RVs in KNDC1 and nominally significant linkage (p < 0.05) was observed with RVs in LOAD genes ABCA7 and IQCK. When AAO of AD was analyzed for APOE ε4 positive family members, nominally significant linkage was observed with RVs in APOE, while when AAO of AD was analyzed for APOE ε4 negative family members, nominal significance was observed for IQCK and ADAMTS1. RV-QNPL provides a powerful resource to analyze QTs in families to elucidate their genetic etiology.
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http://dx.doi.org/10.1038/s41431-020-0703-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785016PMC
December 2020

A Rare Variant Nonparametric Linkage Method for Nuclear and Extended Pedigrees with Application to Late-Onset Alzheimer Disease via WGS Data.

Am J Hum Genet 2019 10;105(4):822-835

Center for Statistical Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neurology, Taub Institute on Alzheimer Disease and the Aging Brain, and Gertrude H. Sergievsky Center, Columbia University, New York, NY 10027, USA; Center for Statistical Genetics, Columbia University, New York, NY 10027, USA. Electronic address:

To analyze family-based whole-genome sequence (WGS) data for complex traits, we developed a rare variant (RV) non-parametric linkage (NPL) analysis method, which has advantages over association methods. The RV-NPL differs from the NPL in that RVs are analyzed, and allele sharing among affected relative-pairs is estimated only for minor alleles. Analyzing families can increase power because causal variants with familial aggregation usually have larger effect sizes than those underlying sporadic diseases. Differing from association analysis, for NPL only affected individuals are analyzed, which can increase power, since unaffected family members can be susceptibility variant carriers. RV-NPL is robust to population substructure and admixture, inclusion of nonpathogenic variants, as well as allelic and locus heterogeneity and can readily be applied outside of coding regions. In contrast to analyzing common variants using NPL, where loci localize to large genomic regions (e.g., >50 Mb), mapped regions are well defined for RV-NPL. Using simulation studies, we demonstrate that RV-NPL is substantially more powerful than applying traditional NPL methods to analyze RVs. The RV-NPL was applied to analyze 107 late-onset Alzheimer disease (LOAD) pedigrees of Caribbean Hispanic and European ancestry with WGS data, and statistically significant linkage (LOD ≥ 3.8) was found with RVs in PSMF1 and PTPN21 which have been shown to be involved in LOAD etiology. Additionally, nominally significant linkage was observed with RVs in ABCA7, ACE, EPHA1, and SORL1, genes that were previously reported to be associated with LOAD. RV-NPL is an ideal method to elucidate the genetic etiology of complex familial diseases.
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http://dx.doi.org/10.1016/j.ajhg.2019.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817540PMC
October 2019

Rare Variants Imputation in Admixed Populations: Comparison Across Reference Panels and Bioinformatics Tools.

Front Genet 2019 3;10:239. Epub 2019 Apr 3.

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States.

Background: Imputation has become a standard approach in genome-wide association studies (GWAS) to infer untyped markers. Although feasibility for common variants imputation is well established, we aimed to assess rare and ultra-rare variants' imputation in an admixed Caribbean Hispanic population (CH).

Methods: We evaluated imputation accuracy in CH ( = 1,000), focusing on rare (0.1% ≤ minor allele frequency (MAF) ≤ 1%) and ultra-rare (MAF < 0.1%) variants. We used two reference panels, the Haplotype Reference Consortium (HRC; = 27,165) and 1000 Genome Project (1000G phase 3; = 2,504) and multiple phasing (SHAPEIT, Eagle2) and imputation algorithms (IMPUTE2, MACH-Admix). To assess imputation quality, we reported: (a) high-quality variant counts according to imputation tools' internal indexes (e.g., IMPUTE2 "Info" ≥ 80%). (b) Wilcoxon Signed-Rank Test comparing imputation quality for genotyped variants that were masked and imputed; (c) Cohen's kappa coefficient to test agreement between imputed and whole-exome sequencing (WES) variants; (d) imputation of G206A mutation in the (ultra-rare in the general population an more frequent in CH) followed by confirmation genotyping. We also tested ancestry proportion (European, African and Native American) against WES-imputation mismatches in a Poisson regression fashion.

Results: SHAPEIT2 retrieved higher percentage of imputed high-quality variants than Eagle2 (rare: 51.02% vs. 48.60%; ultra-rare 0.66% vs. 0.65%, Wilcoxon -value < 0.001). SHAPEIT-IMPUTE2 employing HRC outperformed 1000G (64.50% vs. 59.17%; 1.69% vs. 0.75% for high-quality rare and ultra-rare variants, respectively, Wilcoxon -value < 0.001). SHAPEIT-IMPUTE2 outperformed MaCH-Admix. Compared to 1000G, HRC-imputation retrieved a higher number of high-quality rare and ultra-rare variants, despite showing lower agreement between imputed and WES variants (e.g., rare: 98.86% for HRC vs. 99.02% for 1000G). High Kappa ( = 0.99) was observed for both reference panels. Twelve G206A mutation carriers were imputed and all validated by confirmation genotyping. African ancestry was associated with higher imputation errors for uncommon and rare variants (-value < 1e-05).

Conclusion: Reference panels with larger numbers of haplotypes can improve imputation quality for rare and ultra-rare variants in admixed populations such as CH. Ethnic composition is an important predictor of imputation accuracy, with higher African ancestry associated with poorer imputation accuracy.
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http://dx.doi.org/10.3389/fgene.2019.00239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456789PMC
April 2019

Association of Rare Coding Mutations With Alzheimer Disease and Other Dementias Among Adults of European Ancestry.

JAMA Netw Open 2019 03 1;2(3):e191350. Epub 2019 Mar 1.

Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts.

Importance: Some of the unexplained heritability of Alzheimer disease (AD) may be due to rare variants whose effects are not captured in genome-wide association studies because very large samples are needed to observe statistically significant associations.

Objective: To identify genetic variants associated with AD risk using a nonstatistical approach.

Design, Setting, And Participants: Genetic association study in which rare variants were identified by whole-exome sequencing in unrelated individuals of European ancestry from the Alzheimer's Disease Sequencing Project (ADSP). Data were analyzed between March 2017 and September 2018.

Main Outcomes And Measures: Minor alleles genome-wide and in 95 genes previously associated with AD, AD-related traits, or other dementias were tabulated and filtered for predicted functional impact and occurrence in participants with AD but not controls. Support for several findings was sought in a whole-exome sequencing data set comprising 19 affected relative pairs from Utah high-risk pedigrees and whole-genome sequencing data sets from the ADSP and Alzheimer's Disease Neuroimaging Initiative.

Results: Among 5617 participants with AD (3202 [57.0%] women; mean [SD] age, 76.4 [9.3] years) and 4594 controls (2719 [59.0%] women; mean [SD] age, 86.5 [4.5] years), a total of 24 variants with moderate or high functional impact from 19 genes were observed in 10 or more participants with AD but not in controls. These variants included a missense mutation (rs149307620 [p.A284T], n = 10) in NOTCH3, a gene in which coding mutations are associated with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), that was also identified in 1 participant with AD and 1 participant with mild cognitive impairment in the whole genome sequencing data sets. Four participants with AD carried the TREM2 rs104894002 (p.Q33X) high-impact mutation that, in homozygous form, causes Nasu-Hakola disease, a rare disorder characterized by early-onset dementia and multifocal bone cysts, suggesting an intermediate inheritance model for the mutation. Compared with controls, participants with AD had a significantly higher burden of deleterious rare coding variants in dementia-associated genes (2314 vs 3354 cumulative variants, respectively; P = .006).

Conclusions And Relevance: Different mutations in the same gene or variable dose of a mutation may be associated with result in distinct dementias. These findings suggest that minor differences in the structure or amount of protein may be associated with in different clinical outcomes. Understanding these genotype-phenotype associations may provide further insight into the pathogenic nature of the mutations, as well as offer clues for developing new therapeutic targets.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.1350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450321PMC
March 2019

Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.

Nat Genet 2019 03 28;51(3):414-430. Epub 2019 Feb 28.

Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades-Universitat Internacional de Catalunya, Barcelona, Spain.

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
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http://dx.doi.org/10.1038/s41588-019-0358-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463297PMC
March 2019

A rare missense variant of CASP7 is associated with familial late-onset Alzheimer's disease.

Alzheimers Dement 2019 03 3;15(3):441-452. Epub 2019 Jan 3.

Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; Department of Neurology, Boston University School of Medicine, Boston, MA, USA; Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA; Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA. Electronic address:

Introduction: The genetic architecture of Alzheimer's disease (AD) is only partially understood.

Methods: We conducted an association study for AD using whole sequence data from 507 genetically enriched AD cases (i.e., cases having close relatives affected by AD) and 4917 cognitively healthy controls of European ancestry (EA) and 172 enriched cases and 179 controls of Caribbean Hispanic ancestry. Confirmation of top findings from stage 1 was sought in two family-based genome-wide association study data sets and in a whole genome-sequencing data set comprising members from 42 EA and 115 Caribbean Hispanic families.

Results: We identified associations in EAs with variants in 12 novel loci. The most robust finding is a rare CASP7 missense variant (rs116437863; P = 2.44 × 10) which improved when combined with results from stage 2 data sets (P = 1.92 × 10).

Discussion: Our study demonstrated that an enriched case design can strengthen genetic signals, thus allowing detection of associations that would otherwise be missed in a traditional case-control study.
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http://dx.doi.org/10.1016/j.jalz.2018.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6408965PMC
March 2019

Ancestral origin of ApoE ε4 Alzheimer disease risk in Puerto Rican and African American populations.

PLoS Genet 2018 12 5;14(12):e1007791. Epub 2018 Dec 5.

John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, United States of America.

The ApoE ε4 allele is the most significant genetic risk factor for late-onset Alzheimer disease. The risk conferred by ε4, however, differs across populations, with populations of African ancestry showing lower ε4 risk compared to those of European or Asian ancestry. The cause of this heterogeneity in risk effect is currently unknown; it may be due to environmental or cultural factors correlated with ancestry, or it may be due to genetic variation local to the ApoE region that differs among populations. Exploring these hypotheses may lead to novel, population-specific therapeutics and risk predictions. To test these hypotheses, we analyzed ApoE genotypes and genome-wide array data in individuals from African American and Puerto Rican populations. A total of 1,766 African American and 220 Puerto Rican individuals with late-onset Alzheimer disease, and 3,730 African American and 169 Puerto Rican cognitively healthy individuals (> 65 years) participated in the study. We first assessed average ancestry across the genome ("global" ancestry) and then tested it for interaction with ApoE genotypes. Next, we assessed the ancestral background of ApoE alleles ("local" ancestry) and tested if ancestry local to ApoE influenced Alzheimer disease risk while controlling for global ancestry. Measures of global ancestry showed no interaction with ApoE risk (Puerto Rican: p-value = 0.49; African American: p-value = 0.65). Conversely, ancestry local to the ApoE region showed an interaction with the ApoE ε4 allele in both populations (Puerto Rican: p-value = 0.019; African American: p-value = 0.005). ApoE ε4 alleles on an African background conferred a lower risk than those with a European ancestral background, regardless of population (Puerto Rican: OR = 1.26 on African background, OR = 4.49 on European; African American: OR = 2.34 on African background, OR = 3.05 on European background). Factors contributing to the lower risk effect in the ApoE gene ε4 allele are likely due to ancestry-specific genetic factors near ApoE rather than non-genetic ethnic, cultural, and environmental factors.
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http://dx.doi.org/10.1371/journal.pgen.1007791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281216PMC
December 2018

The APOE ε4 allele is associated with a reduction in FEV1/FVC in women: A cross-sectional analysis of the Long Life Family Study.

PLoS One 2018 9;13(11):e0206873. Epub 2018 Nov 9.

Laboratory of Asthma and Lung Inflammation, Pulmonary Branch, National Heart, Lung, and Blood Institute, Bethesda, MD, United States of America.

Introduction: Murine studies have shown that apolipoprotein E modulates pulmonary function during development, aging, and allergen-induced airway disease. It is not known whether the polymorphic human APOE gene influences pulmonary function.

Objectives: We assessed whether an association exists between the polymorphic human APOE ε2, ε3, and ε4 alleles and pulmonary function among participants in the Long Life Family Study.

Methods: Data from 4,468 Caucasian subjects who had genotyping performed for the APOE ε2, ε3, and ε4 alleles were analyzed, with and without stratification by sex. Statistical models were fitted considering the effects of the ε2 allele, defined as ε2/2 or ε2/3 genotypes, and the ε4 allele, defined as ε3/4 or ε4/4 genotypes, which were compared to the ε3/3 genotype.

Results: The mean FEV1/FVC ratio (the forced expiratory volume in one second divided by the forced vital capacity) was lower among women with the ε4 allele as compared to women with the ε3/3 genotype or the ε2 allele. Carriage of the APOE ε4 allele was associated with FEV1/FVC, which implied lower values. Further analysis showed that the association primarily reflected women without lung disease who were older than 70 years. The association was not mediated by lipid levels, smoking status, body mass index, or cardiovascular disease.

Conclusions: This study for the first time identifies that the APOE gene is associated with modified lung physiology in women. This suggests that a link may exist between the APOE ε4 allele, female sex, and a reduction in the FEV1/FVC ratio in older individuals.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0206873PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226172PMC
April 2019

A multi-omic atlas of the human frontal cortex for aging and Alzheimer's disease research.

Sci Data 2018 08 7;5:180142. Epub 2018 Aug 7.

Rush Alzehimer Disease Center, RUSH University, 600 South Paulina Street, Chicago IL 60612, USA.

We initiated the systematic profiling of the dorsolateral prefrontal cortex obtained from a subset of autopsied individuals enrolled in the Religious Orders Study (ROS) or the Rush Memory and Aging Project (MAP), which are jointly designed prospective studies of aging and dementia with detailed, longitudinal cognitive phenotyping during life and a quantitative, structured neuropathologic examination after death. They include over 3,322 subjects. Here, we outline the first generation of data including genome-wide genotypes (n=2,090), whole genome sequencing (n=1,179), DNA methylation (n=740), chromatin immunoprecipitation with sequencing using an anti-Histone 3 Lysine 9 acetylation (H3K9Ac) antibody (n=712), RNA sequencing (n=638), and miRNA profile (n=702). Generation of other omic data including ATACseq, proteomic and metabolomics profiles is ongoing. Thanks to its prospective design and recruitment of older, non-demented individuals, these data can be repurposed to investigate a large number of syndromic and quantitative neuroscience phenotypes. The many subjects that are cognitively non-impaired at death also offer insights into the biology of the human brain in older non-impaired individuals.
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http://dx.doi.org/10.1038/sdata.2018.142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080491PMC
August 2018

Pedigree Selection and Information Content.

Curr Protoc Hum Genet 2018 04;97(1):e56

Department of Biostatistics and Epidemiology, Case Western Reserve University, Cleveland, Ohio.

In this article, we discuss strategies for selection of families and family members for genetic studies. We will evaluate strategies to sample large families with multiply affected members, sibships, and nuclear families. In addition, we have added a section to discuss sub-sampling within pedigrees for large sequencing studies, particularly when genome-wide SNP chips are available on all members of a pedigree. The type of family sampled for a study will determine the statistical analyses and power of discovery of genetic findings. We will evaluate study designs that maximize power and allow for linkage and association analyses to identify genetic loci predisposing to phenotype. © 2018 by John Wiley & Sons, Inc.
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http://dx.doi.org/10.1002/cphg.56DOI Listing
April 2018

Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer's disease.

Ann Clin Transl Neurol 2018 Jul 24;5(7):832-842. Epub 2018 May 24.

The Taub Institute for Research on Alzheimer's Disease and the Aging Brain College of Physicians and Surgeons Columbia University The New York Presbyterian Hospital New York New York.

Objective: The genetic bases of Alzheimer's disease remain uncertain. An international effort to fully articulate genetic risks and protective factors is underway with the hope of identifying potential therapeutic targets and preventive strategies. The goal here was to identify and characterize the frequency and impact of rare and ultra-rare variants in Alzheimer's disease, using whole-exome sequencing in 20,197 individuals.

Methods: We used a gene-based collapsing analysis of loss-of-function ultra-rare variants in a case-control study design with data from the Washington Heights-Inwood Columbia Aging Project, the Alzheimer's Disease Sequencing Project and unrelated individuals from the Institute of Genomic Medicine at Columbia University.

Results: We identified 19 cases carrying extremely rare loss-of-function variants among a collection of 6,965 cases and a single loss-of-function variant among 13,252 controls ( = 2.17 × 10; OR: 36.2 [95% CI: 5.8-1493.0]). Age-at-onset was 7 years earlier for patients with qualifying variant compared with noncarriers. No other gene attained a study-wide level of statistical significance, but multiple top-ranked genes, including , and were among candidates for follow-up studies.

Interpretation: This study implicates ultra-rare, loss-of-function variants in as a significant genetic risk factor for Alzheimer's disease and provides a comprehensive dataset comparing the burden of rare variation in nearly all human genes in Alzheimer's disease cases and controls. This is the first investigation to establish a genome-wide statistically significant association between multiple extremely rare loss-of-function variants in and Alzheimer's disease in a large whole-exome study of unrelated cases and controls.
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http://dx.doi.org/10.1002/acn3.582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043775PMC
July 2018

A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease.

Mol Psychiatry 2020 03 9;25(3):629-639. Epub 2018 Jul 9.

Department of Psychiatry and Psychotherapy, Saarland University Hospital, Saarland University, Homburg, Germany.

Common variants of about 20 genes contributing to AD risk have so far been identified through genome-wide association studies (GWAS). However, there is still a large proportion of heritability that might be explained by rare but functionally important variants. One of the so far identified genes with rare AD causing variants is ADAM10. Using whole-genome sequencing we now identified a single rare nonsynonymous variant (SNV) rs142946965 [p.R215I] in ADAM17 co-segregating with an autosomal-dominant pattern of late-onset AD in one family. Subsequent genotyping and analysis of available whole-exome sequencing data of additional case/control samples from Germany, UK, and USA identified five variant carriers among AD patients only. The mutation inhibits pro-protein cleavage and the formation of the active enzyme, thus leading to loss-of-function of ADAM17 alpha-secretase. Further, we identified a strong negative correlation between ADAM17 and APP gene expression in human brain and present in vitro evidence that ADAM17 negatively controls the expression of APP. As a consequence, p.R215I mutation of ADAM17 leads to elevated Aß formation in vitro. Together our data supports a causative association of the identified ADAM17 variant in the pathogenesis of AD.
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http://dx.doi.org/10.1038/s41380-018-0091-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042727PMC
March 2020

Analysis of shared heritability in common disorders of the brain.

Science 2018 06;360(6395)

Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.
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http://dx.doi.org/10.1126/science.aap8757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097237PMC
June 2018

Analysis of pedigree data in populations with multiple ancestries: Strategies for dealing with admixture in Caribbean Hispanic families from the ADSP.

Genet Epidemiol 2018 09 3;42(6):500-515. Epub 2018 Jun 3.

Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington.

Multipoint linkage analysis is an important approach for localizing disease-associated loci in pedigrees. Linkage analysis, however, is sensitive to misspecification of marker allele frequencies. Pedigrees from recently admixed populations are particularly susceptible to this problem because of the challenge of accurately accounting for population structure. Therefore, increasing emphasis on use of multiethnic samples in genetic studies requires reevaluation of best practices, given data currently available. Typical strategies have been to compute allele frequencies from the sample, or to use marker allele frequencies determined by admixture proportions averaged over the entire sample. However, admixture proportions vary among pedigrees and throughout the genome in a family-specific manner. Here, we evaluate several approaches to model admixture in linkage analysis, providing different levels of detail about ancestral origin. To perform our evaluations, for specification of marker allele frequencies, we used data on 67 Caribbean Hispanic admixed families from the Alzheimer's Disease Sequencing Project. Our results show that choice of admixture model has an effect on the linkage analysis results. Variant-specific admixture proportions, computed for individual families, provide the most detailed regional admixture estimates, and, as such, are the most appropriate allele frequencies for linkage analysis. This likely decreases the number of false-positive results, and is straightforward to implement.
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http://dx.doi.org/10.1002/gepi.22133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160322PMC
September 2018

Quality control and integration of genotypes from two calling pipelines for whole genome sequence data in the Alzheimer's disease sequencing project.

Genomics 2019 07 29;111(4):808-818. Epub 2018 May 29.

Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA; Human Genetics Center, University of Texas Health Science Center, Houston, TX, USA.

The Alzheimer's Disease Sequencing Project (ADSP) performed whole genome sequencing (WGS) of 584 subjects from 111 multiplex families at three sequencing centers. Genotype calling of single nucleotide variants (SNVs) and insertion-deletion variants (indels) was performed centrally using GATK-HaplotypeCaller and Atlas V2. The ADSP Quality Control (QC) Working Group applied QC protocols to project-level variant call format files (VCFs) from each pipeline, and developed and implemented a novel protocol, termed "consensus calling," to combine genotype calls from both pipelines into a single high-quality set. QC was applied to autosomal bi-allelic SNVs and indels, and included pipeline-recommended QC filters, variant-level QC, and sample-level QC. Low-quality variants or genotypes were excluded, and sample outliers were noted. Quality was assessed by examining Mendelian inconsistencies (MIs) among 67 parent-offspring pairs, and MIs were used to establish additional genotype-specific filters for GATK calls. After QC, 578 subjects remained. Pipeline-specific QC excluded ~12.0% of GATK and 14.5% of Atlas SNVs. Between pipelines, ~91% of SNV genotypes across all QCed variants were concordant; 4.23% and 4.56% of genotypes were exclusive to Atlas or GATK, respectively; the remaining ~0.01% of discordant genotypes were excluded. For indels, variant-level QC excluded ~36.8% of GATK and 35.3% of Atlas indels. Between pipelines, ~55.6% of indel genotypes were concordant; while 10.3% and 28.3% were exclusive to Atlas or GATK, respectively; and ~0.29% of discordant genotypes were. The final WGS consensus dataset contains 27,896,774 SNVs and 3,133,926 indels and is publicly available.
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http://dx.doi.org/10.1016/j.ygeno.2018.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397097PMC
July 2019

Whole genome sequencing of Caribbean Hispanic families with late-onset Alzheimer's disease.

Ann Clin Transl Neurol 2018 Apr 13;5(4):406-417. Epub 2018 Mar 13.

The Taub Institute for Research on Alzheimer's Disease and the Aging Brain New York.

Objective: To identify rare causal variants underlying known loci that segregate with late-onset Alzheimer's disease (LOAD) in multiplex families.

Methods: We analyzed whole genome sequences (WGS) from 351 members of 67 Caribbean Hispanic (CH) families from Dominican Republic and New York multiply affected by LOAD. Members of 67 CH and additional 47 Caucasian families underwent WGS as a part of the Alzheimer's Disease Sequencing Project (ADSP). All members of 67 CH families, an additional 48 CH families and an independent CH case-control cohort were subsequently genotyped for validation. Patients met criteria for LOAD, and controls were determined to be dementia free. We investigated rare variants segregating within families and gene-based associations with disease within LOAD GWAS loci.

Results: A variant in p.R434W, segregated significantly with LOAD in two large families (OR = 5.77, 95% CI: 1.07-30.9, = 0.041). In addition, missense mutations in and under previously reported linkage peaks at 7q14.3 and 11q12.3 segregated completely in one family and in follow-up genotyping both were nominally significant ( < 0.05). We also identified rare variants in a number of genes associated with LOAD in prior genome wide association studies, including ( = 0.049), ( = 0.0098) and ( = 0.040).

Conclusions And Relevance: Rare variants in multiple genes influence the risk of LOAD disease in multiplex families. These results suggest that rare variants may underlie loci identified in genome wide association studies.
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http://dx.doi.org/10.1002/acn3.537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899906PMC
April 2018

Genetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer's Disease Sequencing Project.

Dement Geriatr Cogn Disord 2018 27;45(1-2):1-17. Epub 2018 Feb 27.

University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Background/aims: The Alzheimer's Disease Sequencing Project (ADSP) aims to identify novel genes influencing Alzheimer's disease (AD). Variants within genes known to cause dementias other than AD have previously been associated with AD risk. We describe evidence of co-segregation and associations between variants in dementia genes and clinically diagnosed AD within the ADSP.

Methods: We summarize the properties of known pathogenic variants within dementia genes, describe the co-segregation of variants annotated as "pathogenic" in ClinVar and new candidates observed in ADSP families, and test for associations between rare variants in dementia genes in the ADSP case-control study. The participants were clinically evaluated for AD, and they represent European, Caribbean Hispanic, and isolate Dutch populations.

Results/conclusions: Pathogenic variants in dementia genes were predominantly rare and conserved coding changes. Pathogenic variants within ARSA, CSF1R, and GRN were observed, and candidate variants in GRN and CHMP2B were nominated in ADSP families. An independent case-control study provided evidence of an association between variants in TREM2, APOE, ARSA, CSF1R, PSEN1, and MAPT and risk of AD. Variants in genes which cause dementing disorders may influence the clinical diagnosis of AD in a small proportion of cases within the ADSP.
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http://dx.doi.org/10.1159/000485503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5971141PMC
October 2018

Ultra-rare mutations in segregate in Caribbean Hispanic families with Alzheimer disease.

Neurol Genet 2017 Oct 24;3(5):e178. Epub 2017 Aug 24.

Taub Institute for Research on Alzheimer's Disease and the Aging Brain (B.N.V., G.T., R. Lefort, P.L.D.J., S.B., D.R.-D., J.H.L., R.C., R. Lantigua, R.M.); Gertrude H. Sergievsky Center (B.N.V., G.T., S.B., D.R.-D., J.H.L., R.C., R.M.); Department of Neurology (P.L.D.J., S.B., R.M.), Department of Psychiatry (R.M.), Department of Systems Biology (B.N.V.), Department of Medicine (R. Lantigua), and Department of Pathology and Cell Biology (R. Lefort, P.L.N.), College of Physicians and Surgeons, Columbia University, New York Presbyterian Hospital; Department of Epidemiology (J.H.L., R.M.), School of Public Health, Columbia University, New York; Tanz Centre for Research in Neurodegenerative Diseases (E.R., P.S.G.-H.) and Department of Medicine (E.R., P.S.G.-H.), University of Toronto, Krembil Discovery Tower, ON, Canada; Department of Clinical Neurosciences (P.S.G.-H.), Cambridge Institute for Medical Research, University of Cambridge, UK; Rush Alzheimer's Disease Center (L.Y., D.A.B.), Rush University Medical Center, Chicago, IL; Program in Medical and Population Genetics (P.L.D.J.), Broad Institute, Cambridge, MA; and School of Medicine (M.M.), Mother and Teacher Pontifical Catholic University, Santiago, Dominican Republic.

Objective: To identify rare coding variants segregating with late-onset Alzheimer disease (LOAD) in Caribbean Hispanic families.

Methods: Whole-exome sequencing (WES) was completed in 110 individuals from 31 Caribbean Hispanic families without homozygous carriers. Rare coding mutations segregating in families were subsequently genotyped in additional families and in an independent cohort of Caribbean Hispanic patients and controls. messenger RNA (mRNA) expression was assessed in whole blood from mutation carriers with LOAD, noncarriers with LOAD, and healthy elderly controls, and also from autopsied brains in 2 clinical neuropathologic cohort studies of aging and dementia.

Results: Ten ultra-rare missense mutations in the Snf2-related , activator protein (), were found in 12 unrelated families. Compared with the frequency in Caribbean Hispanic controls and the Latino population in the Exome Aggregation Consortium, the frequency of mutations among Caribbean Hispanic patients with LOAD was significantly enriched ( = 1.19e-16). mRNA expression of in whole blood was significantly lower in mutation carriers with LOAD, while the expression in whole blood and in the brain was significantly higher in nonmutation carriers with LOAD. Brain expression also correlated with clinical and neuropathologic endophenotypes.

Conclusions: WES in Caribbean Hispanic families with LOAD revealed ultra-rare missense mutations in , a gene expressed in the brain and mutated in Floating-Harbor syndrome. is a potent coactivator of the CREB-binding protein and a regulator of DNA damage response involving ATP-dependent chromatin remodeling. We hypothesize that increased expression in LOAD suggests a compensatory mechanism altered in mutation carriers.
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http://dx.doi.org/10.1212/NXG.0000000000000178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570674PMC
October 2017

Early-Onset Alzheimer Disease and Candidate Risk Genes Involved in Endolysosomal Transport.

JAMA Neurol 2017 09;74(9):1113-1122

John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida.

Importance: Mutations in APP, PSEN1, and PSEN2 lead to early-onset Alzheimer disease (EOAD) but account for only approximately 11% of EOAD overall, leaving most of the genetic risk for the most severe form of Alzheimer disease unexplained. This extreme phenotype likely harbors highly penetrant risk variants, making it primed for discovery of novel risk genes and pathways for AD.

Objective: To search for rare variants contributing to the risk for EOAD.

Design, Setting, And Participants: In this case-control study, whole-exome sequencing (WES) was performed in 51 non-Hispanic white (NHW) patients with EOAD (age at onset <65 years) and 19 Caribbean Hispanic families previously screened as negative for established APP, PSEN1, and PSEN2 causal variants. Participants were recruited from John P. Hussman Institute for Human Genomics, Case Western Reserve University, and Columbia University. Rare, deleterious, nonsynonymous, or loss-of-function variants were filtered to identify variants in known and suspected AD genes, variants in multiple unrelated NHW patients, variants present in 19 Hispanic EOAD WES families, and genes with variants in multiple unrelated NHW patients. These variants/genes were tested for association in an independent cohort of 1524 patients with EOAD, 7046 patients with late-onset AD (LOAD), and 7001 cognitively intact controls (age at examination, >65 years) from the Alzheimer's Disease Genetics Consortium. The study was conducted from January 21, 2013, to October 13, 2016.

Main Outcomes And Measures: Alzheimer disease diagnosed according to standard National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association criteria. Association between Alzheimer disease and genetic variants and genes was measured using logistic regression and sequence kernel association test-optimal gene tests, respectively.

Results: Of the 1524 NHW patients with EOAD, 765 (50.2%) were women and mean (SD) age was 60.0 (4.9) years; of the 7046 NHW patients with LOAD, 4171 (59.2%) were women and mean (SD) age was 77.4 (8.6) years; and of the 7001 NHW controls, 4215 (60.2%) were women and mean (SD) age was 77.4 (8.6) years. The gene PSD2, for which multiple unrelated NHW cases had rare missense variants, was significantly associated with EOAD (P = 2.05 × 10-6; Bonferroni-corrected P value [BP] = 1.3 × 10-3) and LOAD (P = 6.22 × 10-6; BP = 4.1 × 10-3). A missense variant in TCIRG1, present in a NHW patient and segregating in 3 cases of a Hispanic family, was more frequent in EOAD cases (odds ratio [OR], 2.13; 95% CI, 0.99-4.55; P = .06; BP = 0.413), and significantly associated with LOAD (OR, 2.23; 95% CI, 1.37-3.62; P = 7.2 × 10-4; BP = 5.0 × 10-3). A missense variant in the LOAD risk gene RIN3 showed suggestive evidence of association with EOAD after Bonferroni correction (OR, 4.56; 95% CI, 1.26-16.48; P = .02, BP = 0.091). In addition, a missense variant in RUFY1 identified in 2 NHW EOAD cases showed suggestive evidence of an association with EOAD as well (OR, 18.63; 95% CI, 1.62-213.45; P = .003; BP = 0.129).

Conclusions And Relevance: The genes PSD2, TCIRG1, RIN3, and RUFY1 all may be involved in endolysosomal transport-a process known to be important to development of AD. Furthermore, this study identified shared risk genes between EOAD and LOAD similar to previously reported genes, such as SORL1, PSEN2, and TREM2.
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http://dx.doi.org/10.1001/jamaneurol.2017.1518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5691589PMC
September 2017

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.

Nat Genet 2017 09 17;49(9):1373-1384. Epub 2017 Jul 17.

Boston University School of Medicine, Boston, Massachusetts, USA.

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10, odds ratio (OR) = 0.68, minor allele frequency (MAF) = 0.0059, MAF = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10, OR = 1.43, MAF = 0.011, MAF = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10, OR = 1.67, MAF = 0.0143, MAF = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
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http://dx.doi.org/10.1038/ng.3916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669039PMC
September 2017

Transethnic genome-wide scan identifies novel Alzheimer's disease loci.

Alzheimers Dement 2017 Jul 7;13(7):727-738. Epub 2017 Feb 7.

Department of Medicine (Biomedical Genetics), Boston University Schools of Medicine, Boston, MA, USA; Department of Neurological Sciences and Rush Alzheimer's Disease Center, Chicago, IL, USA; National Center for PTSD, Behavioral Science Division, Boston VA Healthcare System, Boston, MA, USA.

Introduction: Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood.

Methods: We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset.

Results: Genome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)-based tests (P < 5 × 10) were identified for SNPs in PFDN1/HBEGF, USP6NL/ECHDC3, and BZRAP1-AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence (P < 2.7 × 10) for gene-based association in the total sample with a novel locus, TPBG (P = 1.8 × 10).

Discussion: Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.
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http://dx.doi.org/10.1016/j.jalz.2016.12.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496797PMC
July 2017

Novel genetic loci associated with hippocampal volume.

Nat Commun 2017 01 18;8:13624. Epub 2017 Jan 18.

Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808, USA.

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r=-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
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http://dx.doi.org/10.1038/ncomms13624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5253632PMC
January 2017

mutations in early- and late-onset Alzheimer disease.

Neurol Genet 2016 Dec 26;2(6):e116. Epub 2016 Oct 26.

John P. Hussman Institute for Human Genomics (M.L.C., R.M.C., B.W.K., P.L.W., H.N.C., M.A.P.-V.), University of Miami Miller School of Medicine, FL; Mental Health & Behavioral Science Service (R.M.C.), Bruce W. Carter VA Medical Center, Miami, FL; The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (B.N.V., R.M.), Gertrude H. Sergievsky Center, Departments of Neurology, Psychiatry, and Epidemiology, College of Physicians and Surgeons, Columbia University, New York, NY; Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine (Y.Z., C.B., P.S.G.-H.), University of Toronto, Ontario, Canada; Cambridge Institute for Medical Research (P.S.G.-H.), Department of Clinical Neurosciences, University of Cambridge, United Kingdom; and Dr. John T. Macdonald Foundation Department of Human Genetics (M.L.C., M.A.P.-V.), Miller School of Medicine, University of Miami, FL.

Objective: To characterize the clinical and molecular effect of mutations in the sortilin-related receptor () gene.

Methods: We performed whole-exome sequencing in early-onset Alzheimer disease (EOAD) and late-onset Alzheimer disease (LOAD) families followed by functional studies of select variants. The phenotypic consequences associated with mutations were characterized based on clinical reviews of medical records. Functional studies were completed to evaluate β-amyloid (Aβ) production and amyloid precursor protein (APP) trafficking associated with mutations.

Results: alterations were present in 2 EOAD families. In one, a SORL1 T588I change was identified in 4 individuals with AD, 2 of whom had parkinsonian features. In the second, an SORL1 T2134 alteration was found in 3 of 4 AD cases, one of whom had postmortem Lewy bodies. Among LOAD cases, 4 individuals with either SORL1 A528T or T947M alterations had parkinsonian features. Functionally, the variants weaken the interaction of the SORL1 protein with full-length APP, altering levels of Aβ and interfering with APP trafficking.

Conclusions: The findings from this study support an important role for mutations in AD pathogenesis by way of altering Aβ levels and interfering with APP trafficking. In addition, the presence of parkinsonian features among select individuals with AD and mutations merits further investigation.
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http://dx.doi.org/10.1212/NXG.0000000000000116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082932PMC
December 2016

Novel genetic loci underlying human intracranial volume identified through genome-wide association.

Nat Neurosci 2016 12 3;19(12):1569-1582. Epub 2016 Oct 3.

Brain Center Rudolf Magnus, Department of Psychiatry, UMC Utrecht, Utrecht, the Netherlands.

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρ = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (N = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.
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http://dx.doi.org/10.1038/nn.4398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5227112PMC
December 2016

ABCA7 frameshift deletion associated with Alzheimer disease in African Americans.

Neurol Genet 2016 Jun 17;2(3):e79. Epub 2016 May 17.

John P. Hussman Institute for Human Genomics (H.N.C., B.W.K., S.R., K.L.H.-N., M.A.K., P.L.W., D.V.B., D.M.D., M.L.C., J.M.V., J.R.G., G.W.B., E.R.M., R.M.C., M.A.P.-V.), Department of Neurology (H.N.C., J.M.V., M.A.P.-V.), Dr. John T. Macdonald Foundation Department of Human Genetics (D.M.D., M.L.C., J.M.V., J.R.G., G.W.B., E.R.M., R.M.C.), Miller School of Medicine, University of Miami, FL; The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (B.N.V., R.M.), Gertrude H. Sergievsky Center, Departments of Neurology, Psychiatry, and Epidemiology, College of Physicians and Surgeons, Columbia University, New York, NY; Department of Pathology and Laboratory Medicine (B.A.D., G.D.S.), University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Department of Biology (R.L., G.S.B., M.A.P.-V.), North Carolina A&T State University, Greensboro, NC; Departments of Medicine, Neurology, Ophthalmology, Genetics & Genomics, Epidemiology, and Biostatistics (L.A.F.), Boston University, MA; and Department of Epidemiology and Biostatistics (J.L.H.), Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, OH.

Objective: To identify a causative variant(s) that may contribute to Alzheimer disease (AD) in African Americans (AA) in the ATP-binding cassette, subfamily A (ABC1), member 7 (ABCA7) gene, a known risk factor for late-onset AD.

Methods: Custom capture sequencing was performed on ∼150 kb encompassing ABCA7 in 40 AA cases and 37 AA controls carrying the AA risk allele (rs115550680). Association testing was performed for an ABCA7 deletion identified in large AA data sets (discovery n = 1,068; replication n = 1,749) and whole exome sequencing of Caribbean Hispanic (CH) AD families.

Results: A 44-base pair deletion (rs142076058) was identified in all 77 risk genotype carriers, which shows that the deletion is in high linkage disequilibrium with the risk allele. The deletion was assessed in a large data set (531 cases and 527 controls) and, after adjustments for age, sex, and APOE status, was significantly associated with disease (p = 0.0002, odds ratio [OR] = 2.13 [95% confidence interval (CI): 1.42-3.20]). An independent data set replicated the association (447 cases and 880 controls, p = 0.0117, OR = 1.65 [95% CI: 1.12-2.44]), and joint analysis increased the significance (p = 1.414 × 10(-5), OR = 1.81 [95% CI: 1.38-2.37]). The deletion is common in AA cases (15.2%) and AA controls (9.74%), but in only 0.12% of our non-Hispanic white cohort. Whole exome sequencing of multiplex, CH families identified the deletion cosegregating with disease in a large sibship. The deleted allele produces a stable, detectable RNA strand and is predicted to result in a frameshift mutation (p.Arg578Alafs) that could interfere with protein function.

Conclusions: This common ABCA7 deletion could represent an ethnic-specific pathogenic alteration in AD.
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http://dx.doi.org/10.1212/NXG.0000000000000079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4871806PMC
June 2016

Genetic variants associated with susceptibility to psychosis in late-onset Alzheimer's disease families.

Neurobiol Aging 2015 Nov 15;36(11):3116.e9-3116.e16. Epub 2015 Aug 15.

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA; Gertrude H. Sergievsky Center, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA; Department of Neurology, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA. Electronic address:

Psychotic symptoms are frequent in late-onset Alzheimer's disease (LOAD) patients. Although the risk for psychosis in LOAD is genetically mediated, no genes have been identified. To identify loci potentially containing genetic variants associated with risk of psychosis in LOAD, a total of 263 families from the National Institute of Aging-LOAD cohort were classified into psychotic (LOAD+P, n = 215) and nonpsychotic (LOAD-P, n = 48) families based on the presence/absence of psychosis during the course of LOAD. The LOAD+P families yielded strong evidence of linkage on chromosome 19q13 (two-point [2-pt] ​logarithm of odds [LOD] = 3.8, rs2285513 and multipoint LOD = 2.7, rs541169). Joint linkage and association in 19q13 region detected strong association with rs2945988 (p = 8.7 × 10(-7)). Linkage results for the LOAD-P families yielded nonsignificant 19q13 LOD scores. Several 19q13 single-nucleotide polymorphisms generalized the association of LOAD+P in a Caribbean Hispanic (CH) cohort, and the strongest signal was rs10410711 (pmeta = 5.1 × 10(-5)). A variant located 24 kb upstream of rs10410711 and rs10421862 was strongly associated with LOAD+P (pmeta = 1.0 × 10(-5)) in a meta-analysis of the CH cohort and an additional non-Hispanic Caucasian dataset. Identified variants rs2945988 and rs10421862 affect brain gene expression levels. Our results suggest that genetic variants in genes on 19q13, some of which are involved in brain development and neurodegeneration, may influence the susceptibility to psychosis in LOAD patients.
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http://dx.doi.org/10.1016/j.neurobiolaging.2015.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4609604PMC
November 2015

F-box/LRR-repeat protein 7 is genetically associated with Alzheimer's disease.

Ann Clin Transl Neurol 2015 Aug 18;2(8):810-20. Epub 2015 Jun 18.

The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, School of Public Health, Columbia University New York, New York ; The Gertrude H. Sergievsky Center, School of Public Health, Columbia University New York, New York ; Department of Neurology, Columbia University New York, New York ; Department of Psychiatry, School of Public Health, Columbia University New York, New York ; Department of Epidemiology, School of Public Health, Columbia University New York, New York.

Objective: In the context of late-onset Alzheimer's disease (LOAD) over 20 genes have been identified but, aside APOE, all show small effect sizes, leaving a large part of the genetic component unexplained. Admixed populations, such as Caribbean Hispanics, can provide a valuable contribution because of their unique genetic profile and higher incidence of the disease. We aimed to identify novel loci associated with LOAD.

Methods: About 4514 unrelated Caribbean Hispanics (2451 cases and 2063 controls) were selected for genome-wide association analysis. Significant loci were further tested in the expanded cohort that also included related family members (n = 5300). Two AD-like transgenic mice models (J20 and rTg4510) were used to study gene expression. Independent data sets of non-Hispanic Whites and African Americans were used to further validate findings, along with publicly available brain expression data sets.

Results: A novel locus, rs75002042 in FBXL7 (5p15.1), was found genome-wide significant in the case-control cohort (odd ratio [OR] = 0.61, P = 6.19E-09) and confirmed in the related members cohorts (OR = 0.63, P = 4.7E-08). Fbxl7 protein was overexpressed in both AD-like transgenic mice compared to wild-type littermates. Publicly available microarray studies also showed significant overexpression of Fbxl7 in LOAD brains compared to nondemented controls. single-nucleotide polymorphism (SNP) rs75002042 was in complete linkage disequilibrium with other variants in two independent non-Hispanic White and African American data sets (0.0005 < P < 0.02) used for replication.

Interpretation: FBXL7, encodes a subcellular protein involved in phosphorylation-dependent ubiquitination processes and displays proapoptotic activity. F-box proteins also modulate inflammation and innate immunity, which may be important in LOAD pathogenesis. Further investigations are needed to validate and understand its role in this and other populations.
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http://dx.doi.org/10.1002/acn3.223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4554442PMC
August 2015

Rare coding mutations identified by sequencing of Alzheimer disease genome-wide association studies loci.

Ann Neurol 2015 Sep 28;78(3):487-98. Epub 2015 Jul 28.

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY.

Objective: To detect rare coding variants underlying loci detected by genome-wide association studies (GWAS) of late onset Alzheimer disease (LOAD).

Methods: We conducted targeted sequencing of ABCA7, BIN1, CD2AP, CLU, CR1, EPHA1, MS4A4A/MS4A6A, and PICALM in 3 independent LOAD cohorts: 176 patients from 124 Caribbean Hispanics families, 120 patients and 33 unaffected individuals from the 129 National Institute on Aging LOAD Family Study; and 263 unrelated Canadian individuals of European ancestry (210 sporadic patients and 53 controls). Rare coding variants found in at least 2 data sets were genotyped in independent groups of ancestry-matched controls. Additionally, the Exome Aggregation Consortium was used as a reference data set for population-based allele frequencies.

Results: Overall we detected a statistically significant 3.1-fold enrichment of the nonsynonymous mutations in the Caucasian LOAD cases compared with controls (p = 0.002) and no difference in synonymous variants. A stop-gain mutation in ABCA7 (E1679X) and missense mutation in CD2AP (K633R) were highly significant in Caucasian LOAD cases, and mutations in EPHA1 (P460L) and BIN1 (K358R) were significant in Caribbean Hispanic families with LOAD. The EPHA1 variant segregated completely in an extended Caribbean Hispanic family and was also nominally significant in the Caucasians. Additionally, BIN1 (K358R) segregated in 2 of the 6 Caribbean Hispanic families where the mutations were discovered.

Interpretation: Targeted sequencing of confirmed GWAS loci revealed an excess burden of deleterious coding mutations in LOAD, with the greatest burden observed in ABCA7 and BIN1. Identifying coding variants in LOAD will facilitate the creation of tractable models for investigation of disease-related mechanisms and potential therapies.
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http://dx.doi.org/10.1002/ana.24466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4546546PMC
September 2015
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