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Updated: Nov 6, 2025
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A Strategy to Identify de Novo Mutations in Common Disorders such as Autism and Schizophrenia
Published on: June 15, 2011
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A tipping point in neuropsychiatric genetics.
Jon M McClellan1, Mary-Claire King2
1Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
Neuron
|May 6, 2021
Summary
Researchers studied schizophrenia in a founder population, identifying rare, severe alleles shared by a few patients. A protocadherin allele implicated in neural circuit defects showed impaired cellular aggregation.
Area of Science:
- Neuroscience
- Genetics
- Psychiatry
Background:
- Severe neuropsychiatric disorders exhibit significant genetic heterogeneity, with most patients having unique disease-associated alleles.
- Studying founder populations can facilitate the identification of rare genetic variants within specific patient groups.
Purpose of the Study:
- To investigate the genetic underpinnings of schizophrenia in the Ashkenazi Jewish founder population.
- To identify rare, severe alleles contributing to schizophrenia pathogenesis.
Main Methods:
- Analysis of genetic data from the Ashkenazi Jewish founder population to identify shared rare alleles in schizophrenia patients.
- Experimental validation of an implicated protocadherin allele using cellular aggregation assays.
Main Results:
- Identification of rare, severe alleles associated with schizophrenia, each shared by a subset of patients.
- Experimental evidence showed that the studied protocadherin allele impairs homophilic cellular aggregation.
Conclusions:
- Rare alleles, even when shared by few individuals, can play a significant role in severe neuropsychiatric disorders like schizophrenia.
- Defective homophilic cellular aggregation due to specific alleles may represent a mechanism underlying neural circuit development deficits in schizophrenia.
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