Browsing by Subject "REGULATORY NETWORK"

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  • Cloninger, C. Robert; Cloninger, Kevin M.; Zwir, Igor; Keltikangas-Järvinen, Liisa (2019)
    Recent genome-wide association studies (GWAS) have shown that temperament is strongly influenced by more than 700 genes that modulate associative conditioning by molecular processes for synaptic plasticity and long-term learning and memory. The results were replicated in three independent samples despite variable cultures and environments. The identified genes were enriched in pathways activated by behavioral conditioning in animals, including the two major molecular pathways for response to extracellular stimuli, the Ras-MEK-ERK and the PI3K-AKT-mTOR cascades. These pathways are activated by a wide variety of physiological and psychosocial stimuli that vary in positive and negative valence and in consequences for health and survival. Changes in these pathways are orchestrated to maintain cellular homeostasis despite changing conditions by modulating temperament and its circadian and seasonal rhythms. In this review we first consider traditional concepts of temperament in relation to the new genetic findings by examining the partial overlap of alternative measures of temperament. Then we propose a definition of temperament as the disposition of a person to learn how to behave, react emotionally, and form attachments automatically by associative conditioning. This definition provides necessary and sufficient criteria to distinguish temperament from other aspects of personality that become integrated with it across the life span. We describe the effects of specific stimuli on the molecular processes underlying temperament from functional, developmental, and evolutionary perspectives. Our new knowledge can improve communication among investigators, increase the power and efficacy of clinical trials, and improve the effectiveness of treatment of personality and its disorders.
  • Zwir, Igor; Del-Val, Coral; Arnedo, Javier; Pulkki-Råback, Laura; Konte, Bettina; Yang, Sarah S.; Romero-Zaliz, Rocio; Hintsanen, Mirka; Cloninger, Kevin M.; Garcia, Danilo; Svrakic, Dragan M.; Lester, Nigel; Rozsa, Sandor; Mesa, Alberto; Lyytikainen, Leo-Pekka; Giegling, Ina; Kahonen, Mika; Martinez, Maribel; Seppala, Ilkka; Raitoharju, Emma; de Erausquin, Gabriel A.; Mamah, Daniel; Raitakari, Olli; Rujescu, Dan; Postolache, Teodor T.; Gu, C. Charles; Sung, Joohon; Lehtimäki, Terho; Keltikangas-Jarvinen, Liisa; Cloninger, C. Robert (2021)
    Phylogenetic, developmental, and brain-imaging studies suggest that human personality is the integrated expression of three major systems of learning and memory that regulate (1) associative conditioning, (2) intentionality, and (3) self-awareness. We have uncovered largely disjoint sets of genes regulating these dissociable learning processes in different clusters of people with (1) unregulated temperament profiles (i.e., associatively conditioned habits and emotional reactivity), (2) organized character profiles (i.e., intentional self-control of emotional conflicts and goals), and (3) creative character profiles (i.e., self-aware appraisal of values and theories), respectively. However, little is known about how these temperament and character components of personality are jointly organized and develop in an integrated manner. In three large independent genome-wide association studies from Finland, Germany, and Korea, we used a data-driven machine learning method to uncover joint phenotypic networks of temperament and character and also the genetic networks with which they are associated. We found three clusters of similar numbers of people with distinct combinations of temperament and character profiles. Their associated genetic and environmental networks were largely disjoint, and differentially related to distinct forms of learning and memory. Of the 972 genes that mapped to the three phenotypic networks, 72% were unique to a single network. The findings in the Finnish discovery sample were blindly and independently replicated in samples of Germans and Koreans. We conclude that temperament and character are integrated within three disjoint networks that regulate healthy longevity and dissociable systems of learning and memory by nearly disjoint sets of genetic and environmental influences.
  • Zwir, Igor; Arnedo, Javier; Del-Val, Coral; Pulkki-Råback, Laura; Konte, Bettina; Yang, Sarah S.; Romero-Zaliz, Rocio; Hintsanen, Mirka; Cloninger, Kevin M.; Garcia, Danilo; Svrakic, Dragan M.; Rozsa, Sandor; Martinez, Maribel; Lyytikäinen, Leo-Pekka; Giegling, Ina; Kähönen, Mika; Hernandez-Cuervo, Helena; Seppälä, Ilkka; Raitoharju, Emma; de Erausquin, Gabriel A.; Raitakari, Olli; Rujescu, Dan; Postolache, Teodor T.; Sung, Joohon; Keltikangas-Jarvinen, Liisa; Lehtimäki, Terho; Cloninger, C. Robert (2020)
    Human personality is 30-60% heritable according to twin and adoption studies. Hundreds of genetic variants are expected to influence its complex development, but few have been identified. We used a machine learning method for genome-wide association studies (GWAS) to uncover complex genotypic-phenotypic networks and environmental interactions. The Temperament and Character Inventory (TCI) measured the self-regulatory components of personality critical for health (i.e., the character traits of self-directedness, cooperativeness, and self-transcendence). 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 five clusters of people with distinct profiles of character traits regardless of genotype. Third, we found 42 SNP sets that identified 727 gene loci and were significantly associated with one or more of the character profiles. Each character profile was related to different SNP sets with distinct molecular processes and neuronal functions. Environmental influences measured in childhood and adulthood had small but significant effects. We confirmed the replicability of 95% of the 42 SNP sets in healthy Korean and German samples, as well as their associations with character. The identified SNPs explained nearly all the heritability expected for character in each sample (50 to 58%). We conclude that self-regulatory personality traits are strongly influenced by organized interactions among more than 700 genes despite variable cultures and environments. These gene sets modulate specific molecular processes in brain for intentional goal-setting, self-reflection, empathy, and episodic learning and memory.
  • Zwir, Igor; Arnedo, Javier; Del-Val, Coral; Pulkki-Raback, Laura; Konte, Bettina; Yang, Sarah S.; Romero-Zaliz, Rocio; Hintsanen, Mirka; Cloninger, Kevin M.; Garcia, Danilo; Svrakic, Dragan M.; Rozsa, Sandor; Martinez, Maribel; Lyytikäinen, Leo-Pekka; Giegling, Ina; Kähönen, Mika; Hernandez-Cuervo, Helena; Seppälä, Ilkka; Raitoharju, Emma; de Erausquin, Gabriel A.; Raitakari, Olli; Rujescu, Dan; Postolache, Teodor T.; Sung, Joohon; Keltikangas-Jarvinen, Liisa; Lehtimäki, Terho; Cloninger, C. Robert (2020)
    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.