scholarly journals The complex genetics and biology of human temperament: a review of traditional concepts in relation to new molecular findings

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
C. Robert Cloninger ◽  
Kevin M. Cloninger ◽  
Igor Zwir ◽  
Liisa Keltikangas-Järvinen
Keyword(s):  
Association Studies ◽  
Genome Wide Association Studies ◽  
Molecular Processes ◽  
Complex Genetics ◽  
Associative Conditioning ◽  
Necessary And Sufficient Criteria ◽  
Alternative Measures ◽  
Positive And Negative Valence ◽  
Partial Overlap ◽  
Definition Of

Abstract 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.

scholarly journals Uncovering the complex genetics of human character

2018 ◽  
Vol 25 (10) ◽  
pp. 2295-2312 ◽  
Author(s):  
Igor Zwir ◽  
Javier Arnedo ◽  
Coral Del-Val ◽  
Laura Pulkki-Råback ◽  
Bettina Konte ◽  
...  
Keyword(s):  
Association Studies ◽  
Character Traits ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Molecular Processes ◽  
Adoption Studies ◽  
Complex Genetics ◽  
Discovery Sample ◽  
Character Inventory ◽  
Self Transcendence

AbstractHuman 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.

scholarly journals Uncovering the complex genetics of human temperament

2018 ◽  
Vol 25 (10) ◽  
pp. 2275-2294 ◽  
Author(s):  
Igor Zwir ◽  
Javier Arnedo ◽  
Coral Del-Val ◽  
Laura Pulkki-Råback ◽  
Bettina Konte ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Association Studies ◽  
Experimental Studies ◽  
Long Term Memory ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Complex Genetics ◽  
Associative Conditioning ◽  
Discovery Sample ◽  
Character Inventory

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.

scholarly journals Cystic Fibrosis Disease Modifiers: Complex Genetics Defines the Phenotypic Diversity in a Monogenic Disease

2018 ◽  
Vol 19 (1) ◽  
pp. 201-222 ◽  
Author(s):  
Wanda K. O'Neal ◽  
Michael R. Knowles
Keyword(s):  
Cystic Fibrosis ◽  
Phenotypic Diversity ◽  
Association Studies ◽  
Gene Mutations ◽  
Monogenic Disease ◽  
Genome Wide Association Studies ◽  
Complex Genetics ◽  
Genetic Components ◽  
Significant Gene ◽  
Gene Expression Studies

In many respects, genetic studies in cystic fibrosis (CF) serve as a paradigm for a human Mendelian genetic success story. From recognition of the condition as a heritable pathological entity to implementation of personalized treatments based on genetic findings, this multistep pathway of progress has focused on the genetic underpinnings of CF clinical disease. Along this path was the recognition that not all CFTR gene mutations produce the same disease and the recognition of the complex, multifactorial nature of CF genotype–phenotype relationships. The non- CFTR genetic components (gene modifiers) that contribute to variation in phenotype are the focus of this review. A multifaceted approach involving candidate gene studies, genome-wide association studies, and gene expression studies has revealed significant gene modifiers for multiple CF phenotypes. The bold challenges for the future are to integrate the findings into our understanding of CF pathogenesis and to use the knowledge to develop novel therapies.

Results of the BRD CAP project: progress toward identifying genetic markers associated with BRD susceptibility

2014 ◽  
Vol 15 (2) ◽  
pp. 157-160 ◽  
Author(s):  
Alison Van Eenennaam ◽  
Holly Neibergs ◽  
Christopher Seabury ◽  
Jeremy Taylor ◽  
Zeping Wang ◽  
...  
Keyword(s):  
Association Studies ◽  
Clinical Signs ◽  
The United States ◽  
Feedlot Cattle ◽  
United States Department ◽  
Genome Wide Association Studies ◽  
Dairy Calf ◽  
Definition Of ◽  
Genetic Evaluations ◽  
Quantitative Definition

AbstractThe Bovine Respiratory Disease Coordinated Agricultural Project (BRD CAP) is a 5-year project funded by the United States Department of Agriculture (USDA), with an overriding objective to use the tools of modern genomics to identify cattle that are less susceptible to BRD. To do this, two large genome wide association studies (GWAS) were conducted using a case:control design on preweaned Holstein dairy heifers and beef feedlot cattle. A health scoring system was used to identify BRD cases and controls. Heritability estimates for BRD susceptibility ranged from 19 to 21% in dairy calves to 29.2% in beef cattle when using numerical scores as a semi-quantitative definition of BRD. A GWAS analysis conducted on the dairy calf data showed that single nucleotide polymorphism (SNP) effects explained 20% of the variation in BRD incidence and 17–20% of the variation in clinical signs. These results represent a preliminary analysis of ongoing work to identify loci associated with BRD. Future work includes validation of the chromosomal regions and SNPs that have been identified as important for BRD susceptibility, fine mapping of chromosomes to identify causal SNPs, and integration of predictive markers for BRD susceptibility into genetic tests and national cattle genetic evaluations.

scholarly journals Privacy-Preserving Data Sharing for Genome-Wide Association Studies

2013 ◽  
Vol 5 (1) ◽  
Author(s):  
Caroline Uhler ◽  
Aleksandra B. Slavkovic ◽  
Stephen E. Fienberg
Keyword(s):  
Differential Privacy ◽  
Association Studies ◽  
Simulated Data ◽  
Privacy Preserving ◽  
External Information ◽  
Genome Wide Association Studies ◽  
Chi Square ◽  
Gwas Study ◽  
Genome Wide ◽  
Definition Of

Traditional statistical methods for confidentiality protection of statistical databases do not scale well to deal with GWAS databases especially in terms of guarantees regarding protection from linkage to external information. The more recent concept of differential privacy, introduced by the cryptographic community, is an approach which provides a rigorous definition of privacy with meaningful privacy guarantees in the presence of arbitrary external information, although the guarantees may come at a serious price in terms of data utility. Building on such notions, we propose new methods to release aggregate GWAS data without compromising an individual’s privacy. We present methods for releasing differentially private minor allele frequencies, chi-square statistics and p-values. We compare these approaches on simulated data and on a GWAS study of canine hair length involving 685 dogs. We also propose a privacy-preserving method for finding genome-wide associations based on a differentially-private approach to penalized logistic regression.

ECP06-01 - Genomewide - asscociation studies of psychiatric phenotypes: What they have told us and what to do next

2011 ◽  
Vol 26 (S2) ◽  
pp. 1803-1803
Author(s):  
T.G. Schulze
Keyword(s):  
Psychiatric Disorders ◽  
Disease Risk ◽  
Association Studies ◽  
Future Research ◽  
Allelic Heterogeneity ◽  
List Type ◽  
Genome Wide Association Studies ◽  
Monogenic Disorders ◽  
Complex Genetics ◽  
Risk Alleles

Genome-wide association studies of psychiatric disorders have highlighted several novel susceptibility genes and taught us several importnat lessons.1)Psychiatric disorders are polygenic disorders. The contribution of each locus to risk of disease is modest and disease risk increases substantially with the total burden of risk alleles carried.2)The best findings from GWAS do not necessarily fall within those genes that have previously been widely studied.3)Pursuing a “top-hits-only” strategy may prevent us from understanding the genetic complexity of psychiatric disorders and polygenic disorders in general. A detailed consideration of the wider distribution of association signals across studies may prove to be a valuable strategy in complex genetics.4)Allelic heterogeneity may be an important factor in psychiatric disorders. Allelic heterogeneity means that a phenotype can be caused by different alleles within a gene; this phenomenon has been extensively observed in monogenic disorders such as cystic fibrosis as well as in BRCA1/2-associated breast cancer.5)Finally, as with other complex phenotypes, GWAS in psychiatric disorders demonstrate that the variants identified so far only account for a small fraction of genetic variability.Future research will need to embark on several complementary approaches in order to fill the yet “unexplained” part of the variance. These will among others include sequencing projects, pharmacogenetic studies, detailed genotype-phenotype dissection approaches, and the study of prospectively assessed phenotypes.

scholarly journals Estimating FST and kinship for arbitrary population structures

PLoS Genetics ◽  
2021 ◽  
Vol 17 (1) ◽  
pp. e1009241
Author(s):  
Alejandro Ochoa ◽  
John D. Storey
Keyword(s):  
Association Studies ◽  
Data Sets ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Heritability Estimation ◽  
Complex Population ◽  
Population Structures ◽  
Definition Of ◽  
Moments Estimators ◽  
Modern Population

FST and kinship are key parameters often estimated in modern population genetics studies in order to quantitatively characterize structure and relatedness. Kinship matrices have also become a fundamental quantity used in genome-wide association studies and heritability estimation. The most frequently-used estimators of FST and kinship are method-of-moments estimators whose accuracies depend strongly on the existence of simple underlying forms of structure, such as the independent subpopulations model of non-overlapping, independently evolving subpopulations. However, modern data sets have revealed that these simple models of structure likely do not hold in many populations, including humans. In this work, we analyze the behavior of these estimators in the presence of arbitrarily-complex population structures, which results in an improved estimation framework specifically designed for arbitrary population structures. After generalizing the definition of FST to arbitrary population structures and establishing a framework for assessing bias and consistency of genome-wide estimators, we calculate the accuracy of existing FST and kinship estimators under arbitrary population structures, characterizing biases and estimation challenges unobserved under their originally-assumed models of structure. We then present our new approach, which consistently estimates kinship and FST when the minimum kinship value in the dataset is estimated consistently. We illustrate our results using simulated genotypes from an admixture model, constructing a one-dimensional geographic scenario that departs nontrivially from the independent subpopulations model. Our simulations reveal the potential for severe biases in estimates of existing approaches that are overcome by our new framework. This work may significantly improve future analyses that rely on accurate kinship and FST estimates.

scholarly journals Genetics and psychosis

2014 ◽  
Vol 20 (1) ◽  
pp. 69-70
Author(s):  
Alastair G. Cardno
Keyword(s):  
Psychotic Disorders ◽  
Association Studies ◽  
Molecular Genetic ◽  
Genetic Research ◽  
Copy Number Variants ◽  
Genetic Influences ◽  
Genome Wide Association Studies ◽  
Adoption Studies ◽  
Genome Wide ◽  
Partial Overlap

SummaryGenetic research into psychotic disorders is advancing rapidly. On the basis of general evidence for genetic influences from family, twin and adoption studies, molecular genetic studies, particularly genome-wide association studies (GWAS), are identifying a range of common genetic risk factors that each have a small effect on risk, while certain chromosomal copy number variants (CNVs) are rarer, but have a larger effect on risk. There is also evidence for partial overlap of genetic influences among psychotic disorders and with non-psychotic disorders. This brief article summarises the main themes, current findings and potential future directions.

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