Identifying loci with different allele frequencies among cases of eight psychiatric disorders using CC-GWAS

Wouter J. Peyrot, Alkes L. Price

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43 Citations (Scopus)


Psychiatric disorders are highly genetically correlated, but little research has been conducted on the genetic differences between disorders. We developed a new method (case–case genome-wide association study; CC-GWAS) to test for differences in allele frequency between cases of two disorders using summary statistics from the respective case–control GWAS, transcending current methods that require individual-level data. Simulations and analytical computations confirm that CC-GWAS is well powered with effective control of type I error. We applied CC-GWAS to publicly available summary statistics for schizophrenia, bipolar disorder, major depressive disorder and five other psychiatric disorders. CC-GWAS identified 196 independent case–case loci, including 72 CC-GWAS-specific loci that were not significant at the genome-wide level in the input case–control summary statistics; two of the CC-GWAS-specific loci implicate the genes KLF6 and KLF16 (from the Krüppel-like family of transcription factors), which have been linked to neurite outgrowth and axon regeneration. CC-GWAS loci replicated convincingly in applications to datasets with independent replication data.
Original languageEnglish
Pages (from-to)445-454
Number of pages10
JournalNature Genetics
Issue number4
Early online date8 Mar 2021
Publication statusPublished - 1 Apr 2021


  • Alleles
  • Axons/metabolism
  • Bipolar Disorder/genetics
  • Case-Control Studies
  • Datasets as Topic
  • Depressive Disorder, Major/genetics
  • Gene Expression
  • Gene Frequency
  • Genetic Loci
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Kruppel-Like Factor 6/genetics
  • Kruppel-Like Transcription Factors/genetics
  • Neuronal Outgrowth/genetics
  • Polymorphism, Single Nucleotide
  • Schizophrenia/genetics

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