scholarly journals Mapping Risk from Genes to Behavior: The Enduring and Evolving Influence of Irving Gottesman's Endophenotype Concept

2018 ◽  
Vol 21 (4) ◽  
pp. 306-309 ◽  
Author(s):  
Danielle M. Dick
Keyword(s):  
Large Scale ◽  
Behavior Genetics ◽  
Disease Model ◽  
Behavioral Outcomes ◽  
Disease Etiology ◽  
Genome Wide ◽  
Sufficient Power ◽  
Polygenic Scores ◽  
Clinical Diagnoses ◽  
Psychiatric Outcomes

One of Irving I. Gottesman's many contributions to behavior genetics, and part of his enduring legacy, was his introduction of the term ‘endophenotype’ to the field of psychiatry. Gottesman argued that focusing on endophenotypes, rather than complex heterogeneous clinical diagnoses, could help elucidate disease etiology. Although a different strategy for gene identification ultimately proved successful (that of amassing extremely large sample sizes in order to overcome the ‘noise’ of heterogeneity and have sufficient power to find genes of very small effect), the endophenotype concept continues to make a meaningful contribution to the field. The endophenotype concept forced the field to move beyond a simple disease model of finding genes ‘for’ psychiatric outcomes, and reminded us that genes are quite distal from complex behavioral outcomes and disorders. Endophenotypes called our attention to the steps along that pathway. In that process, the concept of endophenotypes evolved and expanded to include discussion of the role that other intermediary traits and psychological processes play in the development and genetic etiology of psychiatric and substance use disorders. As large-scale consortia continues to identify genes and generate genome-wide polygenic scores that are associated with behavioral outcomes, the next important step will be to characterize the pathways and mechanisms by which genetic risk unfolds. This essential step of mapping risk from genes to behavior is an evolution that follows naturally from the endophenotype concept, and could ultimately translate into improved prevention and intervention for individuals who are pre-disposed to mental health challenges.

scholarly journals Polygenic scores for handedness and their association with asymmetries in brain structure

2021 ◽  
Author(s):  
Sebastian Ocklenburg ◽  
Dorothea Metzen ◽  
Caroline Schlüter ◽  
Christoph Fraenz ◽  
Larissa Arning ◽  
...  
Keyword(s):  
Brain Structure ◽  
Large Scale ◽  
Validation Cohort ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Genetic Determinants ◽  
Independent Validation ◽  
Genome Wide ◽  
Polygenic Scores ◽  
First Time

AbstractHandedness is the most widely investigated motor preference in humans. The genetics of handedness and especially the link between genetic variation, brain structure, and right-left preference have not been investigated in detail. Recently, several well-powered genome-wide association studies (GWAS) on handedness have been published, significantly advancing the understanding of the genetic determinants of left and right-handedness. In the present study, we estimated polygenic scores (PGS) of handedness-based on the GWAS by de Kovel and Francks (Sci Rep 9: 5986, 2019) in an independent validation cohort (n = 296). PGS reflect the sum effect of trait-associated alleles across many genetic loci. For the first time, we could show that these GWAS-based PGS are significantly associated with individual handedness lateralization quotients in an independent validation cohort. Additionally, we investigated whether handedness-derived polygenic scores are associated with asymmetries in gray matter macrostructure across the whole brain determined using magnetic resonance imaging. None of these associations reached significance after correction for multiple comparisons. Our results implicate that PGS obtained from large-scale handedness GWAS are significantly associated with individual handedness in smaller validation samples with more detailed phenotypic assessment.

scholarly journals Brain transcriptional regulatory architecture and schizophrenia etiology converge between East Asian and European ancestral populations

2021 ◽  
Author(s):  
Sihan Liu ◽  
Yu Chen ◽  
Feiran Wang ◽  
Yi Jiang ◽  
Fangyuan Duan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Large Scale ◽  
Association Studies ◽  
Allelic Frequency ◽  
Genome Wide Association Studies ◽  
Disease Etiology ◽  
Risk Genes ◽  
Regulatory Architecture ◽  
Genome Wide ◽  
Transcriptional Regulatory

AbstractUnderstanding the genetic architecture of gene expression and splicing in human brain is critical to unlocking the mechanisms of complex neuropsychiatric disorders like schizophrenia (SCZ). Large-scale brain transcriptomic studies are based primarily on populations of European (EUR) ancestry. The uniformity of mono-racial resources may limit important insights into the disease etiology. Here, we characterized brain transcriptional regulatory architecture of East Asians (EAS; n=151), identifying 3,278 expression quantitative trait loci (eQTL) and 4,726 spliceQTL (sQTL). Comparing these to PsychENCODE/BrainGVEX confirmed our hypothesis that the transcriptional regulatory architecture in EAS and EUR brains align. Furthermore, distinctive allelic frequency and linkage disequilibrium impede QTL translation and gene-expression prediction accuracy. Integration of eQTL/sQTL with genome-wide association studies reveals common and novel SCZ risk genes. Pathway-based analyses showing shared SCZ biology point to synaptic and GTPase dysfunction as a prospective pathogenesis. This study elucidates the transcriptional landscape of the EAS brain and emphasizes an essential convergence between EAS and EUR populations.

scholarly journals Unraveling the polygenic architecture of complex traits using blood eQTL metaanalysis

2018 ◽  
Author(s):  
Urmo Võsa ◽  
Annique Claringbould ◽  
Harm-Jan Westra ◽  
Marc Jan Bonder ◽  
Patrick Deelen ◽  
...  
Keyword(s):  
Complex Traits ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Complex Trait ◽  
Genome Wide Association ◽  
Eqtl Analysis ◽  
Genome Wide Association Studies ◽  
Disease Etiology ◽  
Genome Wide ◽  
Polygenic Scores

SummaryWhile many disease-associated variants have been identified through genome-wide association studies, their downstream molecular consequences remain unclear.To identify these effects, we performedcis-andtrans-expressionquantitative trait locus (eQTL) analysis in blood from 31,684 individuals through the eQTLGen Consortium.We observed thatcis-eQTLs can be detected for 88% of the studied genes, but that they have a different genetic architecture compared to disease-associated variants, limiting our ability to usecis-eQTLs to pinpoint causal genes within susceptibility loci.In contrast, trans-eQTLs (detected for 37% of 10,317 studied trait-associated variants) were more informative. Multiple unlinked variants, associated to the same complex trait, often converged on trans-genes that are known to play central roles in disease etiology.We observed the same when ascertaining the effect of polygenic scores calculated for 1,263 genome-wide association study (GWAS) traits. Expression levels of 13% of the studied genes correlated with polygenic scores, and many resulting genes are known to drive these traits.

scholarly journals Current Polygenic Scores Fail to Capture Resilience

2020 ◽  
Author(s):  
Brianna Bucknor ◽  
Jaime Derringer
Keyword(s):  
Individual Differences ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Molecular Genetic ◽  
Population Sample ◽  
Psychological Variables ◽  
Genetic Predictors ◽  
Genome Wide ◽  
Polygenic Scores ◽  
Starting Point

Stress is a well-known risk factor for the development of psychopathology (Harkness, Hayden, & Lopez-Duran, 2015). However, not everyone who is exposed to stress responds in the same way. Individual differences in resilience to stress reflect dynamic interpersonal and intrapersonal factors (Laird, Krause, Funes, & Lavretsky, 2019). Although resilience has been identified to be moderately heritable (30-50%; Boardman, Blalock, & Button, 2008), little is known about the genetic variants that may explain this heritability. While there has not yet been a robust genome-wide association study (GWAS) of resilience, existing GWAS of related phenotypes (proxies) may provide a starting point for developing our understanding of the molecular genetic underpinnings of the observed heritability of resilience. In a population sample of older US adults (N= 9,480), we examined the extent to which 32 polygenic proxy scores explained the variance in resilience. We then compared the utility of these existing genetic predictors to commonly examined demographic and psychological characteristics, such as socioeconomic status and social support. We found that the psychological correlates consistently and substantially outperformed existing polygenic scores. While psychological variables yielded substantial correlations with resilience, only four of the 32 polygenic scores reached significance but with relatively small effects. Our results indicate that existing polygenic scores are not sufficient to inform our understanding of resilience, nor would they be suitable predictors of individual differences in resilience outcomes. We conclude that a large-scale GWAS of resilience will be necessary to identify the specific genetics underlying the observed heritability of resilience.

scholarly journals Do Low Polygenic Scores Buffer the Effects of Maltreatment? A Polygene-Environment Interaction Study of ADHD

2021 ◽  
Author(s):  
Quanfa He ◽  
James Janford Li
Keyword(s):  
Genome Wide Association Study ◽  
Alternative Methods ◽  
Future Research ◽  
Environment Interaction ◽  
Adult Health ◽  
Adhd Symptoms ◽  
Social Emotional ◽  
Genome Wide ◽  
Polygenic Scores ◽  
Psychiatric Outcomes

Objective: This study explored whether maltreatment moderates the association of polygenic risk for ADHD. Because individuals with low polygenic scores (PGS) for ADHD were previously shown to have better than expected functional outcomes (i.e., cognitive, mental health, social-emotional) than individuals with middle or high ADHD PGS, we hypothesized that low ADHD PGS may possible confer a protective effect against maltreatment in the development of ADHD. Method: Data were from participants with phenotypic and genotypic data in the National Longitudinal Study of Adolescent to Adult Health (Add Health; n=4,722), which was used to examine the effects of ADHD PGS, maltreatment, and their interaction on childhood ADHD symptoms. ADHD PGS were generated from the most recent genome-wide association study on ADHD and categorized into three groups (i.e., low, medium, high) using empirically determined cut-points. A maltreatment factor score was derived from five forms of self-reported maltreatment experiences prior to age 18. Results: ADHD PGS and maltreatment were positively associated with ADHD symptoms, as expected. However, we did not detect an interaction between ADHD PGS and maltreatment on ADHD symptoms. Conclusion: Despite the increase in predictive power afforded by PGS, the lack of an interaction between ADHD PGS and maltreatment on ADHD symptoms converges with an emerging body of psychiatric PGS studies that have also failed to detect polygenic-environment interplay on psychiatric outcomes. We discuss possible reasons for this pattern of results and offer alternative methods for future research in revealing important polygenic-environment interactions for ADHD.

Wellness Dimensions Relate to Large-Scale Achievement and Behavioral Outcomes

2014 ◽  
Author(s):  
Eric Vreeman ◽  
Robert Brett Nelson ◽  
Donna Schnorr
Keyword(s):  
Large Scale ◽  
Behavioral Outcomes

scholarly journals The Genetic Basis of Hypertriglyceridemia

2021 ◽  
Vol 23 (8) ◽  
Author(s):  
Germán D. Carrasquilla ◽  
Malene Revsbech Christiansen ◽  
Tuomas O. Kilpeläinen
Keyword(s):  
Genetic Basis ◽  
Association Studies ◽  
Cumulative Effect ◽  
Genome Wide Association Studies ◽  
Genetic Loci ◽  
Risk Variants ◽  
Genome Wide ◽  
Severe Hypertriglyceridemia ◽  
Increased Risk ◽  
Polygenic Scores

Abstract Purpose of Review Hypertriglyceridemia is a common dyslipidemia associated with an increased risk of cardiovascular disease and pancreatitis. Severe hypertriglyceridemia may sometimes be a monogenic condition. However, in the vast majority of patients, hypertriglyceridemia is due to the cumulative effect of multiple genetic risk variants along with lifestyle factors, medications, and disease conditions that elevate triglyceride levels. In this review, we will summarize recent progress in the understanding of the genetic basis of hypertriglyceridemia. Recent Findings More than 300 genetic loci have been identified for association with triglyceride levels in large genome-wide association studies. Studies combining the loci into polygenic scores have demonstrated that some hypertriglyceridemia phenotypes previously attributed to monogenic inheritance have a polygenic basis. The new genetic discoveries have opened avenues for the development of more effective triglyceride-lowering treatments and raised interest towards genetic screening and tailored treatments against hypertriglyceridemia. Summary The discovery of multiple genetic loci associated with elevated triglyceride levels has led to improved understanding of the genetic basis of hypertriglyceridemia and opened new translational opportunities.

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