ArticleGenome research2022
An association test of the spatial distribution of rare missense variants within protein structures identifies Alzheimer's disease-related patterns.
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Article in Genome research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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2citing papers in PubMed
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2 citing papers in PubMed, 5 citations in OpenAlex.
- Statistical methods for assessing the effects of de novo variants on birth defects.Human genomics · 2024Review
- Pharmacogenomic and Statistical Analysis.Methods in molecular biology (Clifton, N.J.) · 2023Article
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Authors and funding
19 authors at 6 institutions in 1 country.
Bowen JinGraduate Program in Systems Biology and Bioinformatics, Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA.ORCID 0000-0003-1442-6259
John A CapraThe Bakar Computational Health Sciences Institute, Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California 94143, USA.ORCID 0000-0001-9743-1795
Penelope BenchekCleveland Institute for Computational Biology, Department for Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Nicholas WheelerCleveland Institute for Computational Biology, Department for Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Adam C NajDepartment of Pathology and Laboratory Medicine, Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.ORCID 0000-0002-9621-2942
Kara L Hamilton-NelsonThe John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA.
John J FarrellDepartment of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Yuk Yee LeungDepartment of Pathology and Laboratory Medicine, Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Brian KunkleThe John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA.
Badri VadarajanTaub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology, Gertrude H. Sergievsky Center, Department of Neurology, Columbia University, New York, New York 10032, USA.
Gerard D SchellenbergDepartment of Pathology and Laboratory Medicine, Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Richard MayeuxTaub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology, Gertrude H. Sergievsky Center, Department of Neurology, Columbia University, New York, New York 10032, USA.
Li-San WangDepartment of Pathology and Laboratory Medicine, Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Lindsay A FarrerDepartment of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Margaret A Pericak-VanceThe John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA.
Eden R MartinThe John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA.
Jonathan L HainesCleveland Institute for Computational Biology, Department for Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Dana C CrawfordCleveland Institute for Computational Biology, Department for Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio 44106, USA.
William S BushCleveland Institute for Computational Biology, Department for Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio 44106, USA.ORCID 0000-0002-9729-6519
Case Western Reserve University · USUniversity of Miami · USUniversity of Pennsylvania · USBoston University · USColumbia University · USUniversity of California, San Francisco · US
Funding
Large Scale Sequencing and Analysis of GenomesU54HG003067 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI GABRIEL, STACEY, LANDER, ERIC S · 2004 to 2015
$568.6MLarge Scale Genome SequencingU54HG003079 · NHGRI · WASHINGTON UNIVERSITY · PI DUTCHER, SUSAN K · 2004 to 2016
$445.7MThe Human Genome Sequencing CenterU54HG003273 · NHGRI · BAYLOR COLLEGE OF MEDICINE · PI GIBBS, RICHARD A · 2004 to 2015
$341.3MProject 1U19AG024904 · NIA · NORTHERN CALIFORNIA INSTITUTE/RES/EDU · PI MICHAEL W WEINER · 2016 to 2026
$226.7MNational Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD)U24AG021886 · NIA · INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS · PI TATIANA M. FOROUD · 2002 to 2026
$119.8MVCID and Stroke in a Bi-racial National CohortU01NS041588 · NINDS · UNIVERSITY OF ALABAMA AT BIRMINGHAM · PI CUSHMAN, MARY, HOWARD, GEORGE · 2002 to 2022
$96.0MNATIONAL ALZHEIMERS COORDINATING CENTER (NACC)U01AG016976 · NIA · UNIVERSITY OF WASHINGTON · PI KUKULL, WALTER ANTHONY · 1999 to 2020
$72.8MARIC Neurocognitive Study (ARIC-NCS) Renewal 2023-2028U01HL096812 · NHLBI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI JOSEF CORESH, THOMAS H MOSLEY · 2010 to 2026
$65.7MAlzheimer's Disease Genetics ConsortiumU01AG032984 · NIA · UNIVERSITY OF PENNSYLVANIA · PI SCHELLENBERG, GERARD DAVID · 2009 to 2024
$60.4MTHERAPEUTIC EFFECTS OF INTRA-NASAL INSULIN DETEMIRP50AG005136 · NIA · UNIVERSITY OF WASHINGTON · PI JAYADEY, SUMAN · 1985 to 2019
$57.2MVIRUS-INDUCED BRAIN PATHOLOGYP50AG005131 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI BREWER, JAMES B · 1985 to 2018
$55.4MWASHINGTON UNIVERSITY ALZHEIMERS DISEASE RESEARCH CENTERP50AG005681 · NIA · WASHINGTON UNIVERSITY · PI MORRIS, JOHN · 1985 to 2019
$52.1MAustrian Science Fund FWF I 904NHGRI NIH HHS RC2 HG005605NHGRI NIH HHS U01 HG004610NHGRI NIH HHS U01 HG006375NHGRI NIH HHS U01 HG008657NHGRI NIH HHS U54 HG003067NHGRI NIH HHS U54 HG003079NHGRI NIH HHS U54 HG003273NHLBI NIH HHS HHSN268200800007CNHLBI NIH HHS HHSN268201100005CNHLBI NIH HHS HHSN268201100005GNHLBI NIH HHS HHSN268201100005INHLBI NIH HHS HHSN268201100006CNHLBI NIH HHS HHSN268201100007CNHLBI NIH HHS HHSN268201100007INHLBI NIH HHS HHSN268201100008CNHLBI NIH HHS HHSN268201100008INHLBI NIH HHS HHSN268201100009CNHLBI NIH HHS HHSN268201100009INHLBI NIH HHS HHSN268201100010CNHLBI NIH HHS HHSN268201100011CNHLBI NIH HHS HHSN268201100011INHLBI NIH HHS HHSN268201100012CNHLBI NIH HHS HHSN268201200036CNHLBI NIH HHS HHSN268201500001CNHLBI NIH HHS HHSN268201500001INHLBI NIH HHS N01 HC025195NHLBI NIH HHS N01 HC055222NHLBI NIH HHS N01 HC085079NHLBI NIH HHS N01 HC085080NHLBI NIH HHS N01 HC085081NHLBI NIH HHS N01 HC085082NHLBI NIH HHS N01 HC085083NHLBI NIH HHS N01 HC085086NHLBI NIH HHS R01 HL070825NHLBI NIH HHS R01 HL105756NHLBI NIH HHS RC2 HL102419NHLBI NIH HHS U01 HL080295NHLBI NIH HHS U01 HL096812NHLBI NIH HHS U01 HL096814NHLBI NIH HHS U01 HL096899NHLBI NIH HHS U01 HL096902NHLBI NIH HHS U01 HL096917NHLBI NIH HHS U01 HL130114NIA NIH HHS K23 AG030944NIA NIH HHS P30 AG008017NIA NIH HHS P30 AG008051NIA NIH HHS P30 AG010124NIA NIH HHS P30 AG010129NIA NIH HHS P30 AG010133NIA NIH HHS P30 AG010161NIA NIH HHS P30 AG012300NIA NIH HHS P30 AG013846NIA NIH HHS P30 AG013854NIA NIH HHS P30 AG019610NIA NIH HHS P30 AG028383NIA NIH HHS P30 AG035982NIA NIH HHS P30 AG062422NIA NIH HHS P30 AG066509NIA NIH HHS P30 AG066518NIA NIH HHS P30 AG066546NIA NIH HHS P30 AG072979NIA NIH HHS P50 AG005131NIA NIH HHS P50 AG005133NIA NIH HHS P50 AG005134NIA NIH HHS P50 AG005136NIA NIH HHS P50 AG005138NIA NIH HHS P50 AG005142NIA NIH HHS P50 AG005146NIA NIH HHS P50 AG005681NIA NIH HHS P50 AG008012NIA NIH HHS P50 AG008702NIA NIH HHS P50 AG016570NIA NIH HHS P50 AG016573NIA NIH HHS P50 AG016574NIA NIH HHS P50 AG023501NIA NIH HHS P50 AG025688NIA NIH HHS P50 AG033514NIA NIH HHS P50 AG047266NIA NIH HHS P50 AG047270NIA NIH HHS P50 AG047366NIA NIH HHS R01 AG009029NIA NIH HHS R01 AG009956NIA NIH HHS R01 AG011101NIA NIH HHS R01 AG011380NIA NIH HHS R01 AG015473NIA NIH HHS R01 AG015819NIA NIH HHS R01 AG015928NIA NIH HHS R01 AG017917NIA NIH HHS R01 AG017919NIA NIH HHS R01 AG018016NIA NIH HHS R01 AG019085NIA NIH HHS R01 AG019757NIA NIH HHS R01 AG020098NIA NIH HHS R01 AG021136NIA NIH HHS R01 AG021547NIA NIH HHS R01 AG023629NIA NIH HHS R01 AG025259NIA NIH HHS R01 AG027944NIA NIH HHS R01 AG028786NIA NIH HHS R01 AG031272NIA NIH HHS R01 AG032990NIA NIH HHS R01 AG033040NIA NIH HHS R01 AG033193NIA NIH HHS R01 AG041797NIA NIH HHS R01 AG048927NIA NIH HHS R01 AG049607NIA NIH HHS R01 AG054076NIA NIH HHS R01 AG058066NIA NIH HHS R01 AG067501NIA NIH HHS R03 AG054936NIA NIH HHS R37 AG015473NIA NIH HHS R56 AG051876NIA NIH HHS RC4 AG039085NIA NIH HHS RF1 AG015473NIA NIH HHS RF1 AG051504NIA NIH HHS RF1 AG054023NIA NIH HHS RF1 AG054052NIA NIH HHS RF1 AG054074NIA NIH HHS RF1 AG057519NIA NIH HHS RF1 AG058066NIA NIH HHS RF1 AG058267NIA NIH HHS U01 AG006781NIA NIH HHS U01 AG016976NIA NIH HHS U01 AG032984NIA NIH HHS U01 AG046139NIA NIH HHS U01 AG049505NIA NIH HHS U01 AG049506NIA NIH HHS U01 AG049507NIA NIH HHS U01 AG049508NIA NIH HHS U01 AG052409NIA NIH HHS U01 AG052410NIA NIH HHS U01 AG052411NIA NIH HHS U01 AG057659NIA NIH HHS U01 AG058589NIA NIH HHS U01 AG058635NIA NIH HHS U01 AG058654NIA NIH HHS U01 AG062602NIA NIH HHS U01 AG062943NIA NIH HHS U19 AG024904NIA NIH HHS U24 AG021886NIA NIH HHS U24 AG041689NIA NIH HHS U24 AG056270NIA NIH HHS U54 AG052427NIA NIH HHS UF1 AG047133NIGMS NIH HHS R01 GM126249NINDS NIH HHS P01 NS026630NINDS NIH HHS P50 NS039764NINDS NIH HHS P50 NS071674NINDS NIH HHS R01 NS017950NINDS NIH HHS R01 NS029993NINDS NIH HHS R01 NS069719NINDS NIH HHS R01 NS080820NINDS NIH HHS U01 NS041588NLM NIH HHS R01 LM012535Wellcome Trust
Abstract
More than 90% of genetic variants are rare in most modern sequencing studies, such as the Alzheimer's Disease Sequencing Project (ADSP) whole-exome sequencing (WES) data. Furthermore, 54% of the rare variants in ADSP WES are singletons. However, both single variant and unit-based tests are limited in their statistical power to detect an association between rare variants and phenotypes. To best use missense rare variants and investigate their biological effect, we examine their association with phenotypes in the context of protein structures. We developed a protein structure-based approach, protein optimized kernel evaluation of missense nucleotides (POKEMON), which evaluates rare missense variants based on their spatial distribution within a protein rather than their allele frequency. The hypothesis behind this test is that the three-dimensional spatial distribution of variants within a protein structure provides functional context to power an association test. POKEMON identified three candidate genes (
Indexed as
Alzheimer DiseaseExome SequencingGene FrequencyGenetic Predisposition to DiseaseHumansLDL-Receptor Related ProteinsMembrane Transport ProteinsMutation, MissensePhenotypeLDL-Receptor Related ProteinsMembrane Transport ProteinsSORL1 protein, human
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