Uncovering the complex genetics of human temperament

Igor Zwir, Javier Arnedo, Coral Del-Val, Laura Pulkki-Råback, Bettina Konte, Sarah S. Yang, Rocio Romero-Zaliz, Mirka Hintsanen, Kevin M. Cloninger, Danilo Garcia, Dragan M. Svrakic, Sandor Rozsa, Maribel Martinez, Leo Pekka Lyytikäinen, Ina Giegling, Mika Kähönen, Helena Hernandez-Cuervo, Ilkka Seppälä, Emma Raitoharju, Gabriel A. de ErausquinOlli Raitakari, Dan Rujescu, Teodor T. Postolache, Joohon Sung, Liisa Keltikangas-Järvinen, Terho Lehtimäki, C. Robert Cloninger

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Experimental studies of learning suggest that human temperament may depend on the molecular mechanisms for associative conditioning, which are highly conserved in animals. The main genetic pathways for associative conditioning are known in experimental animals, but have not been identified in prior genome-wide association studies (GWAS) of human temperament. We used a data-driven machine learning method for GWAS to uncover the complex genotypic–phenotypic networks and environmental interactions related to human temperament. In a discovery sample of 2149 healthy Finns, we identified sets of single-nucleotide polymorphisms (SNPs) that cluster within particular individuals (i.e., SNP sets) regardless of phenotype. Second, we identified 3 clusters of people with distinct temperament profiles measured by the Temperament and Character Inventory regardless of genotype. Third, we found 51 SNP sets that identified 736 gene loci and were significantly associated with temperament. The identified genes were enriched in pathways activated by associative conditioning in animals, including the ERK, PI3K, and PKC pathways. 74% of the identified genes were unique to a specific temperament profile. Environmental influences measured in childhood and adulthood had small but significant effects. We confirmed the replicability of the 51 Finnish SNP sets in healthy Korean (90%) and German samples (89%), as well as their associations with temperament. The identified SNPs explained nearly all the heritability expected in each sample (37–53%) despite variable cultures and environments. We conclude that human temperament is strongly influenced by more than 700 genes that modulate associative conditioning by molecular processes for synaptic plasticity and long-term memory.

Original languageEnglish (US)
Pages (from-to)2275-2294
Number of pages20
JournalMolecular psychiatry
Volume25
Issue number10
DOIs
StatePublished - Oct 1 2020

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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