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

Nat Genet. 2021 Apr;53(4):445-454. doi: 10.1038/s41588-021-00787-1. Epub 2021 Mar 8.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • KLF16 protein, human
  • KLF6 protein, human
  • Kruppel-Like Factor 6
  • Kruppel-Like Transcription Factors