ArticleNeuron2021
Novel ultra-rare exonic variants identified in a founder population implicate cadherins in schizophrenia.
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Article in Neuron, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14citing papers in PubMed
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Who cites it
14 citing papers in PubMed, 29 citations in OpenAlex.
- Genetic Variants from Large Cohorts and Familial Studies Implicate Common Mechanisms in Schizophrenia.Biology · 2026Review
- Computational whole-body-exposome models for global precision brain health.Nature communications · 2025Article
- Language, Motor Ability and Related Deficits in Children at Familial Risk of Schizophrenia or Bipolar Disorder.Schizophrenia bulletin · 2025Article
- Demographic, Premorbid, and Clinical Characteristics of Schizophrenia Spectrum Patients with High and Low Polygenic Liability to the Disorder.Diseases (Basel, Switzerland) · 2025Article
- Whole exome sequencing analyses identified novel genes for Alzheimer's disease and related dementia.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Article
- Review
- Fine-scale genetic structure and rare variant frequencies.PloS one · 2024Article
- Article
- The impact of rare protein coding genetic variation on adult cognitive function.Nature genetics · 2023Article
- Copy Number Variations and Schizophrenia.Molecular neurobiology · 2023Review
- The Difficult Path to the Discovery of Novel Treatments in Psychiatric Disorders.Advances in neurobiology · 2023Article
- Assessment of burden and segregation profiles of CNVs in patients with epilepsy.Annals of clinical and translational neurology · 2022Article
- Association of DNA Methylation Patterns in 7 Novel Genes With Ischemic Stroke in the Northern Chinese Population.Frontiers in genetics · 2022Article
- The population frequency of human mitochondrial DNA variants is highly dependent upon mutational bias.Biology open · 2021Article
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Authors and funding
24 authors at 11 institutions in 2 countries.
Todd LenczDepartments of Psychiatry and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11550, USA; Department of Psychiatry, Division of Research, The Zucker Hillside Hospital Division of Northwell Health, Glen Oaks, NY 11004, USA; Institute for Behavioral Science, The Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA. Electronic address: tlencz@northwell.edu.
Jin YuDepartment of Psychiatry, Division of Research, The Zucker Hillside Hospital Division of Northwell Health, Glen Oaks, NY 11004, USA; Institute for Behavioral Science, The Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA.
Raiyan Rashid KhanDepartment of Computer Science, Columbia University, New York, NY 10027, USA.
Erin FlahertyDepartment of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Mortimer B. Zuckerman Mind Brain and Behavior Institute, Columbia University, New York, NY 10027, USA.
Shai CarmiBraun School of Public Health and Community Medicine, Faculty of Medicine, Hebrew University of Jerusalem, Ein Kerem, Jerusalem 9112102, Israel.
Max LamDepartment of Psychiatry, Division of Research, The Zucker Hillside Hospital Division of Northwell Health, Glen Oaks, NY 11004, USA; Institute for Behavioral Science, The Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA.
Danny Ben-AvrahamDepartment of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Nir BarzilaiDepartment of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Susan BressmanDepartment of Neurology, Beth Israel Medical Center, New York, NY 10003, USA.
Ariel DarvasiDepartment of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904, Israel.
Judy H ChoInstitute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Lorraine N ClarkDepartment of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Taub Institute for Research of Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY 10032, USA.
Zeynep H GümüşDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Joseph VijaiClinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Robert J KleinDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Taub Institute for Research of Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY 10032, USA.
Steven LipkinDepartments of Medicine, Genetic Medicine and Surgery, Weill Cornell Medical College, New York, NY 10065, USA.
Kenneth OffitClinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Harry OstrerDepartments of Pathology and Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Laurie J OzeliusDepartment of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Inga PeterDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Anil K MalhotraDepartments of Psychiatry and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11550, USA; Department of Psychiatry, Division of Research, The Zucker Hillside Hospital Division of Northwell Health, Glen Oaks, NY 11004, USA; Institute for Behavioral Science, The Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA.
Tom ManiatisDepartment of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Mortimer B. Zuckerman Mind Brain and Behavior Institute, Columbia University, New York, NY 10027, USA; New York Genome Center, New York, NY 10013, USA.
Gil AtzmonDepartment of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Human Biology, Haifa University, Haifa, Israel.
Itsik Pe'erDepartment of Computer Science, Columbia University, New York, NY 10027, USA; Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032, USA. Electronic address: itsik@cs.columbia.edu.
Albert Einstein College of Medicine · USNorthwell Health · USColumbia University · USIcahn School of Medicine at Mount Sinai · USColumbia University Irving Medical Center · USHebrew University of Jerusalem · ILMemorial Sloan Kettering Cancer Center · USCornell University · USMassachusetts General Hospital · USMount Sinai Beth Israel · USNew York Genome Center · US
Funding
X-RAY CRYSTALLOGRAPHYP30CA008748 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI Nicholas D Socci · 1985 to 2026
$347.4MNation Center: Multi-Scale Study- Cellular Networks(RMI)U54CA121852 · NCI · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI CALIFANO, ANDREA · 2005 to 2015
$37.4MInflammatory Bowel Disease Genetics Consortium Data Coordinating CenterU01DK062429 · NIDDK · YALE UNIVERSITY · PI CHO, JUDY H. · 2002 to 2016
$16.8MPrecision IBD via genetics and genomics: integrating International and multi-omic datasets, expanding studies in diverse populations, and defining mechanisms of unmet clinical needs in IBDU24DK062429 · NIDDK · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI Ling-shiang Chuang, Ron Do · 2017 to 2026
$13.9MYale University Inflammatory Bowel Disease Genetics Research CenterU01DK062422 · NIDDK · YALE UNIVERSITY · PI Ling-shiang Chuang · 2002 to 2026
$10.8MEinstein's Nathan Shock Center of Excellence in Basic Biology of AgingP30AG038072 · NIA · ALBERT EINSTEIN COLLEGE OF MEDICINE, INC · PI VIJG, JAN · 2010 to 2024
$10.8MROLE OF NUTRIENTS IN AGE-RELATED INSULIN RESISTANCEP01AG021654 · NIA · YESHIVA UNIVERSITY · PI BARZILAI, NIR J · 2003 to 2007
$10.6MSTATISTICS AND DATA MANAGEMENT COREP01AG027734 · NIA · ALBERT EINSTEIN COLLEGE OF MEDICINE · PI MORROW, BERNICE E · 2007 to 2012
$9.3MThe role of the clustered protocadherins in neural circuit formation and implications for neurodevelopmental disordersR01MH108579 · NIMH · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI MANIATIS, THOMAS P · 2016 to 2025
$5.1MNext Generation Sequencing for Disease Mapping in a Founder PopulationR01MH095458 · NIMH · FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH · PI DARVASI, ARIEL, LENCZ, TODD · 2013 to 2016
$3.8MCommon and Rare Genetic Factors in an Ethnically Homogeneous Schizophrenia CohortRC2MH089964 · NIMH · FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH · PI LENCZ, TODD · 2009 to 2010
$3.5MDefining the genetic architecture of IBD in Ashkenazi Jewish populationsR01DK092235 · NIDDK · YALE UNIVERSITY · PI CHO, JUDY H. · 2012 to 2016
$2.5MNCI NIH HHS P30 CA008748NCI NIH HHS U54 CA121852NIA NIH HHS P01 AG021654NIA NIH HHS P01 AG027734NIA NIH HHS P30 AG038072NIA NIH HHS R01 AG042188NIDDK NIH HHS R01 DK092235NIDDK NIH HHS U01 DK062422NIDDK NIH HHS U01 DK062429NIDDK NIH HHS U24 DK062429NIMH NIH HHS R01 MH084098NIMH NIH HHS R01 MH095458NIMH NIH HHS R01 MH108579NIMH NIH HHS R01 MH114817NIMH NIH HHS RC2 MH089964NINDS NIH HHS R01 NS060113NINDS NIH HHS R21 NS050487
Abstract
The identification of rare variants associated with schizophrenia has proven challenging due to genetic heterogeneity, which is reduced in founder populations. In samples from the Ashkenazi Jewish population, we report that schizophrenia cases had a greater frequency of novel missense or loss of function (MisLoF) ultra-rare variants (URVs) compared to controls, and the MisLoF URV burden was inversely correlated with polygenic risk scores in cases. Characterizing 141 "case-only" genes (MisLoF URVs in ≥3 cases with none in controls), the cadherin gene set was associated with schizophrenia. We report a recurrent case mutation in PCDHA3 that results in the formation of cytoplasmic aggregates and failure to engage in homophilic interactions on the plasma membrane in cultured cells. Modeling purifying selection, we demonstrate that deleterious URVs are greatly overrepresented in the Ashkenazi population, yielding enhanced power for association studies. Identification of the cadherin/protocadherin family as risk genes helps specify the synaptic abnormalities central to schizophrenia.
Indexed as
CadherinsExonsFemaleFounder EffectGenetic Predisposition to DiseaseHumansJewsMaleMutationSchizophreniaCadherinscadherinsexomefounder populationrare variantsschizophrenia
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