scholarly journals Infant Inhibited Temperament in Primates Predicts Adult Behavior, is Heritable, and is Associated with Anxiety-Relevant Genetic Variation

2020 ◽  
Author(s):  
AS Fox ◽  
RA Harris ◽  
L Del Rosso ◽  
M Raveendran ◽  
S Kamboj ◽  
...  
Keyword(s):  
Latent Variables ◽  
Depressive Disorders ◽  
Association Studies ◽  
Single Nucleotide ◽  
Adult Behavior ◽  
Genome Wide ◽  
Family Pedigree ◽  
A Genome ◽  
Human Association

ABSTRACTAn anxious or inhibited temperament (IT) early in life is a major risk factor for the later development of stress-related psychopathology. Starting in infancy, nonhuman primates, like humans, begin to reveal their temperament when exposed to novel situations. Here, in Study 1 we demonstrate this infant IT predicts adult behavior. Specifically, in over 600 monkeys, we found that individuals scored as inhibited during infancy were more likely to refuse treats offered by potentially-threatening human experimenters as adults. In Study 2, using a sample of over 4000 monkeys from a large multi-generational family pedigree, we demonstrate that infant IT is partially heritable. The data revealed infant IT to reflect a co-inherited substrate that manifests across multiple latent variables. Finally, in Study 3 we performed whole-genome sequencing in 106 monkeys to identify IT-associated single-nucleotide variations (SNVs). Results demonstrated a genome-wide significant SNV near CTNNA2, suggesting a molecular target worthy of additional investigation. Moreover, we observed lower p-values in genes implicated in human association studies of neuroticism and depression. Together, these data demonstrate the utility of our model of infant inhibited temperament in the rhesus monkey to facilitate discovery of genes that are relevant to the long-term inherited risk to develop anxiety and depressive disorders.

scholarly journals Infant inhibited temperament in primates predicts adult behavior, is heritable, and is associated with anxiety-relevant genetic variation

2021 ◽  
Author(s):  
Andrew S. Fox ◽  
Ronald A. Harris ◽  
Laura Del Rosso ◽  
Muthuswamy Raveendran ◽  
Shawn Kamboj ◽  
...  
Keyword(s):  
Latent Variables ◽  
Depressive Disorders ◽  
Association Studies ◽  
Single Nucleotide ◽  
Adult Behavior ◽  
Genome Wide ◽  
Family Pedigree ◽  
A Genome ◽  
Human Association

AbstractAn anxious or inhibited temperament (IT) early in life is a major risk factor for the later development of stress-related psychopathology. Starting in infancy, nonhuman primates, like humans, begin to reveal their temperament when exposed to novel situations. Here, in Study 1 we demonstrate this infant IT predicts adult behavior. Specifically, in over 600 monkeys, we found that individuals scored as inhibited during infancy were more likely to refuse treats offered by potentially-threatening human experimenters as adults. In Study 2, using a sample of over 4000 monkeys from a large multi-generational family pedigree, we demonstrate that infant IT is partially heritable. The data revealed infant IT to reflect a co-inherited substrate that manifests across multiple latent variables. Finally, in Study 3 we performed whole-genome sequencing in 106 monkeys to identify IT-associated single-nucleotide variations (SNVs). Results demonstrated a genome-wide significant SNV near CTNNA2, suggesting a molecular target worthy of additional investigation. Moreover, we observed lower p values in genes implicated in human association studies of neuroticism and depression. Together, these data demonstrate the utility of our model of infant inhibited temperament in the rhesus monkey to facilitate discovery of genes that are relevant to the long-term inherited risk to develop anxiety and depressive disorders.

scholarly journals The ANKS1B gene and its associated phenotypes: focus on CNS drug response

2019 ◽  
Vol 20 (9) ◽  
pp. 669-684
Author(s):  
Rabha M Younis ◽  
Rachel M Taylor ◽  
Patrick M Beardsley ◽  
Joseph L McClay
Keyword(s):  
Drug Response ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Functional Studies ◽  
Genome Wide ◽  
Human Association ◽  
Relevant Variation ◽  
Review Current

The ANKS1B gene was a top finding in genome-wide association studies (GWAS) of antipsychotic drug response. Subsequent GWAS findings for ANKS1B include cognitive ability, educational attainment, body mass index, response to corticosteroids and drug dependence. We review current human association evidence for ANKS1B, in addition to functional studies that include two published mouse knockouts. The several GWAS findings in humans indicate that phenotypically relevant variation is segregating at the ANKS1B locus. ANKS1B shows strong plausibility for involvement in CNS drug response because it encodes a postsynaptic effector protein that mediates long-term changes to neuronal biology. Forthcoming data from large biobanks should further delineate the role of ANKS1B in CNS drug response.

scholarly journals Age by Single Nucleotide Polymorphism Interactions on Bronchodilator Response in Asthmatics

2021 ◽  
Vol 11 (1) ◽  
pp. 59
Author(s):  
Kirsten Voorhies ◽  
Joanne E. Sordillo ◽  
Michael McGeachie ◽  
Elizabeth Ampleford ◽  
Alberta L. Wang ◽  
...  
Keyword(s):  
Candidate Genes ◽  
P Value ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Single Nucleotide ◽  
Significance Level ◽  
Bronchodilator Response ◽  
Genome Wide ◽  
A Genome ◽  
Β2 Agonists

An unaddressed and important issue is the role age plays in modulating response to short acting β2-agonists in individuals with asthma. The objective of this study was to identify whether age modifies genetic associations of single nucleotide polymorphisms (SNPs) with bronchodilator response (BDR) to β2-agonists. Using three cohorts with a total of 892 subjects, we ran a genome wide interaction study (GWIS) for each cohort to examine SNP by age interactions with BDR. A fixed effect meta-analysis was used to combine the results. In order to determine if previously identified BDR SNPs had an age interaction, we also examined 16 polymorphisms in candidate genes from two published genome wide association studies (GWAS) of BDR. There were no significant SNP by age interactions on BDR using the genome wide significance level of 5 × 10−8. Using a suggestive significance level of 5 × 10−6, three interactions, including one for a SNP within PRAG1 (rs4840337), were significant and replicated at the significance level of 0.05. Considering candidate genes from two previous GWAS of BDR, three SNPs (rs10476900 (near ADRB2) [p-value = 0.009], rs10827492 (CREM) [p-value = 0.02], and rs72646209 (NCOA3) [p-value = 0.02]) had a marginally significant interaction with age on BDR (p < 0.05). Our results suggest age may be an important modifier of genetic associations for BDR in asthma.

scholarly journals Genetics of complex traits: prediction of phenotype, identification of causal polymorphisms and genetic architecture

2016 ◽  
Vol 283 (1835) ◽  
pp. 20160569 ◽  
Author(s):  
M. E. Goddard ◽  
K. E. Kemper ◽  
I. M. MacLeod ◽  
A. J. Chamberlain ◽  
B. J. Hayes
Keyword(s):  
Complex Traits ◽  
Genetic Architecture ◽  
Quantitative Traits ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Crop Breeding ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Phenotype Identification

Complex or quantitative traits are important in medicine, agriculture and evolution, yet, until recently, few of the polymorphisms that cause variation in these traits were known. Genome-wide association studies (GWAS), based on the ability to assay thousands of single nucleotide polymorphisms (SNPs), have revolutionized our understanding of the genetics of complex traits. We advocate the analysis of GWAS data by a statistical method that fits all SNP effects simultaneously, assuming that these effects are drawn from a prior distribution. We illustrate how this method can be used to predict future phenotypes, to map and identify the causal mutations, and to study the genetic architecture of complex traits. The genetic architecture of complex traits is even more complex than previously thought: in almost every trait studied there are thousands of polymorphisms that explain genetic variation. Methods of predicting future phenotypes, collectively known as genomic selection or genomic prediction, have been widely adopted in livestock and crop breeding, leading to increased rates of genetic improvement.

scholarly journals A publicly available repository of ROH islands reveals signatures of selection in different livestock and pet species

2021 ◽  
Vol 53 (1) ◽  
Author(s):  
Wim Gorssen ◽  
Roel Meyermans ◽  
Steven Janssens ◽  
Nadine Buys
Keyword(s):  
Association Studies ◽  
Genome Wide Association Studies ◽  
Single Nucleotide ◽  
Future Studies ◽  
Snp Data ◽  
Animal Populations ◽  
Genome Wide ◽  
Starting Point ◽  
Different Populations ◽  
Signatures Of Selection

Abstract Background Runs of homozygosity (ROH) have become the state-of-the-art method for analysis of inbreeding in animal populations. Moreover, ROH are suited to detect signatures of selection via ROH islands and are used in other applications, such as genomic prediction and genome-wide association studies (GWAS). Currently, a vast amount of single nucleotide polymorphism (SNP) data is available online, but most of these data have never been used for ROH analysis. Therefore, we performed a ROH analysis on large medium-density SNP datasets in eight animal species (cat, cattle, dog, goat, horse, pig, sheep and water buffalo; 442 different populations) and make these results publicly available. Results The results include an overview of ROH islands per population and a comparison of the incidence of these ROH islands among populations from the same species, which can assist researchers when studying other (livestock) populations or when looking for similar signatures of selection. We were able to confirm many known ROH islands, for example signatures of selection for the myostatin (MSTN) gene in sheep and horses. However, our results also included multiple other ROH islands, which are common to many populations and not identified to date (e.g. on chromosomes D4 and E2 in cats and on chromosome 6 in sheep). Conclusions We are confident that our repository of ROH islands is a valuable reference for future studies. The discovered ROH island regions represent a unique starting point for new studies or can be used as a reference for future studies. Furthermore, we encourage authors to add their population-specific ROH findings to our repository.

scholarly journals A Genome-Wide Scan for Evidence of Selection in a Maize Population Under Long-Term Artificial Selection for Ear Number

Genetics ◽  
2013 ◽  
Vol 196 (3) ◽  
pp. 829-840 ◽  
Author(s):  
Timothy M. Beissinger ◽  
Candice N. Hirsch ◽  
Brieanne Vaillancourt ◽  
Shweta Deshpande ◽  
Kerrie Barry ◽  
...  
Keyword(s):  
Artificial Selection ◽  
Maize Population ◽  
Genome Wide ◽  
A Genome ◽  
Selection For ◽  
Ear Number ◽  
Genome Wide Scan

scholarly journals Challenges of Adjusting Single-Nucleotide Polymorphism Effect Sizes for Linkage Disequilibrium

2021 ◽  
pp. 1-11
Author(s):  
Valentina Escott-Price ◽  
Karl Michael Schmidt
Keyword(s):  
Linkage Disequilibrium ◽  
Association Studies ◽  
Statistical Significance ◽  
Ordinary Least Squares ◽  
Effect Sizes ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Tikhonov Regularisation

<b><i>Background:</i></b> Genome-wide association studies (GWAS) were successful in identifying SNPs showing association with disease, but their individual effect sizes are small and require large sample sizes to achieve statistical significance. Methods of post-GWAS analysis, including gene-based, gene-set and polygenic risk scores, combine the SNP effect sizes in an attempt to boost the power of the analyses. To avoid giving undue weight to SNPs in linkage disequilibrium (LD), the LD needs to be taken into account in these analyses. <b><i>Objectives:</i></b> We review methods that attempt to adjust the effect sizes (β<i>-</i>coefficients) of summary statistics, instead of simple LD pruning. <b><i>Methods:</i></b> We subject LD adjustment approaches to a mathematical analysis, recognising Tikhonov regularisation as a framework for comparison. <b><i>Results:</i></b> Observing the similarity of the processes involved with the more straightforward Tikhonov-regularised ordinary least squares estimate for multivariate regression coefficients, we note that current methods based on a Bayesian model for the effect sizes effectively provide an implicit choice of the regularisation parameter, which is convenient, but at the price of reduced transparency and, especially in smaller LD blocks, a risk of incomplete LD correction. <b><i>Conclusions:</i></b> There is no simple answer to the question which method is best, but where interpretability of the LD adjustment is essential, as in research aiming at identifying the genomic aetiology of disorders, our study suggests that a more direct choice of mild regularisation in the correction of effect sizes may be preferable.

Bisphosphonate-related osteonecrosis of the jaw is associated with polymorphisms of the cytochrome P450 CYP2C8 in multiple myeloma: a genome-wide single nucleotide polymorphism analysis

Blood ◽  
2008 ◽  
Vol 112 (7) ◽  
pp. 2709-2712 ◽  
Author(s):  
Maria E. Sarasquete ◽  
Ramon García-Sanz ◽  
Luis Marín ◽  
Miguel Alcoceba ◽  
Maria C. Chillón ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cytochrome P450 ◽  
Genome Wide Association Study ◽  
Osteonecrosis Of The Jaw ◽  
Bisphosphonate Therapy ◽  
Polymorphism Analysis ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Genome Wide ◽  
A Genome

Abstract We have explored the potential role of genetics in the development of osteonecrosis of the jaw (ONJ) in multiple myeloma (MM) patients under bisphosphonate therapy. A genome-wide association study was performed using 500 568 single nucleotide polymorphisms (SNPs) in 2 series of homogeneously treated MM patients, one with ONJ (22 MM cases) and another without ONJ (65 matched MM controls). Four SNPs (rs1934951, rs1934980, rs1341162, and rs17110453) mapped within the cytochrome P450-2C gene (CYP2C8) showed a different distribution between cases and controls with statistically significant differences (P = 1.07 × 10−6, P = 4.231 × 10−6, P = 6.22 × 10−6, and P = 2.15 × 10−6, respectively). SNP rs1934951 was significantly associated with a higher risk of ONJ development even after Bonferroni correction (P corrected value = .02). Genotyping results displayed an overrepresentation of the T allele in cases compared with controls (48% vs 12%). Thus, individuals homozygous for the T allele had an increased likelihood of developing ONJ (odds ratio 12.75, 95% confidence interval 3.7-43.5).

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