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.