scholarly journals Sensitive period-regulating genetic pathways and exposure to adversity shape risk for depression

2021 ◽  
Author(s):  
Yiwen Zhu ◽  
Min-Jung Wang ◽  
Katherine M Crawford ◽  
Juan Carlos Ramirez-Tapia ◽  
Alexandre A Lussier ◽  
...  
Keyword(s):  
Animal Studies ◽  
Socioeconomic Disadvantage ◽  
Developmental Expression ◽  
Sensitive Period ◽  
Genetic Pathways ◽  
Gene Set ◽  
Sensitive Periods ◽  
Depression Risk ◽  
Genome Wide ◽  
A Genome

Animal and human studies have documented the existence of developmental windows (or sensitive periods) when experience can have lasting effects in shaping brain structure or function, behavior, and disease risk. Sensitive periods for depression likely arise through a complex interplay of genes and experience, though this possibility has not been explored. We examined the effect of sensitive period-regulating genetic pathways identified in preclinical animal studies, alone and in interaction with socioeconomic disadvantage, a common childhood adversity, on depression risk. Using a translational approach, we: (1) performed gene-set association analyses using summary data from a genome-wide association study of depression (n=807,553) to assess the effects of three gene sets (60 genes) shown in animal studies to regulate sensitive periods; (2) evaluated the developmental expression patterns of these sensitive period-regulating genes using data from BrainSpan (n=31), a transcriptional atlas of postmortem brain samples; and (3) tested gene-by-development interplay by analyzing the combined effect of common variants in sensitive period genes and timing of exposure to socioeconomic disadvantage within a population-based birth cohort (n=6254). The gene set regulating sensitive period opening associated with increased depression risk. Notably, six of the 15 genes in this set showed developmentally regulated gene-level expression. A genome-wide polygenic risk score-by-environment analysis showed socioeconomic disadvantage during ages 1-5 years were independently associated with depression risk, but no gene-by-development interactions were found. Genes involved in regulating sensitive periods may be implicated in depression vulnerability and differentially expressed across the life course, though larger studies are needed to identify developmental interplays.

scholarly journals TEGS-CN: A Statistical Method for Pathway Analysis of Genome-wide Copy Number Profile

2014 ◽  
Vol 13s4 ◽  
pp. CIN.S13978
Author(s):  
Yen-Tsung Huang ◽  
Thomas Hsu ◽  
David C. Christiani
Keyword(s):  
Copy Number ◽  
Copy Number Data ◽  
Copy Number Profile ◽  
Test Statistic ◽  
Gene Set ◽  
Bonferroni Adjustment ◽  
Gene Sets ◽  
Genome Wide ◽  
A Genome ◽  
Pathway Analyses

The effects of copy number alterations make up a significant part of the tumor genome profile, but pathway analyses of these alterations are still not well established. We proposed a novel method to analyze multiple copy numbers of genes within a pathway, termed Test for the Effect of a Gene Set with Copy Number data (TEGS-CN). TEGS-CN was adapted from TEGS, a method that we previously developed for gene expression data using a variance component score test. With additional development, we extend the method to analyze DNA copy number data, accounting for different sizes and thus various numbers of copy number probes in genes. The test statistic follows a mixture of X 2 distributions that can be obtained using permutation with scaled X 2 approximation. We conducted simulation studies to evaluate the size and the power of TEGS-CN and to compare its performance with TEGS. We analyzed a genome-wide copy number data from 264 patients of non-small-cell lung cancer. With the Molecular Signatures Database (MSigDB) pathway database, the genome-wide copy number data can be classified into 1814 biological pathways or gene sets. We investigated associations of the copy number profile of the 1814 gene sets with pack-years of cigarette smoking. Our analysis revealed five pathways with significant P values after Bonferroni adjustment (<2.8 x 10-5), including the PTEN pathway (7.8 x 10-7), the gene set up-regulated under heat shock (3.6 x 10-6), the gene sets involved in the immune profile for rejection of kidney transplantation (9.2 x 10-6) and for transcriptional control of leukocytes (2.2 x 10-5), and the ganglioside biosynthesis pathway (2.7 x 10-5). In conclusion, we present a new method for pathway analyses of copy number data, and causal mechanisms of the five pathways require further study.

scholarly journals Heterotaxy in Caenorhabditis : widespread natural variation in left–right arrangement of the major organs

2016 ◽  
Vol 371 (1710) ◽  
pp. 20150404 ◽  
Author(s):  
Melissa R. Alcorn ◽  
Davon C. Callander ◽  
Agustín López-Santos ◽  
Yamila N. Torres Cleuren ◽  
Bilge Birsoy ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Recombinant Inbred Lines ◽  
Sensitive Period ◽  
Temperature Sensitive ◽  
Internal Organs ◽  
Genome Wide ◽  
A Genome ◽  
Natural Isolates ◽  
Left Right Asymmetry ◽  
Genomic Regions

Although the arrangement of internal organs in most metazoans is profoundly left–right (L/R) asymmetric with a predominant handedness, rare individuals show full (mirror-symmetric) or partial (heterotaxy) reversals. While the nematode Caenorhabditis elegans is known for its highly determinate development, including stereotyped L/R organ handedness, we found that L/R asymmetry of the major organs, the gut and gonad, varies among natural isolates of the species in both males and hermaphrodites. In hermaphrodites, heterotaxy can involve one or both bilaterally asymmetric gonad arms. Male heterotaxy is probably not attributable to relaxed selection in this hermaphroditic species, as it is also seen in gonochoristic Caenorhabditis species. Heterotaxy increases in many isolates at elevated temperature, with one showing a pregastrulation temperature-sensitive period, suggesting a very early embryonic or germline effect on this much later developmental outcome. A genome-wide association study of 100 isolates showed that male heterotaxy is associated with three genomic regions. Analysis of recombinant inbred lines suggests that a small number of loci are responsible for the observed variation. These findings reveal that heterotaxy is a widely varying quantitative trait in an animal with an otherwise highly stereotyped anatomy, demonstrating unexpected plasticity in an L/R arrangement of the major organs even in a simple animal. This article is part of the themed issue ‘Provocative questions in left–right asymmetry’.

scholarly journals Genome-wide gene-set analysis for identification of pathways associated with alcohol dependence

2012 ◽  
Vol 16 (2) ◽  
pp. 271-278 ◽  
Author(s):  
Joanna M. Biernacka ◽  
Jennifer Geske ◽  
Gregory D. Jenkins ◽  
Colin Colby ◽  
David N. Rider ◽  
...  
Keyword(s):  
Alcohol Dependence ◽  
Association Studies ◽  
Gene Set Analysis ◽  
Receptor Interaction ◽  
Genome Wide Association Studies ◽  
Addictive Disorders ◽  
Gene Set ◽  
Genome Wide ◽  
Individual Snps ◽  
A Genome

Abstract It is believed that multiple genetic variants with small individual effects contribute to the risk of alcohol dependence. Such polygenic effects are difficult to detect in genome-wide association studies that test for association of the phenotype with each single nucleotide polymorphism (SNP) individually. To overcome this challenge, gene-set analysis (GSA) methods that jointly test for the effects of pre-defined groups of genes have been proposed. Rather than testing for association between the phenotype and individual SNPs, these analyses evaluate the global evidence of association with a set of related genes enabling the identification of cellular or molecular pathways or biological processes that play a role in development of the disease. It is hoped that by aggregating the evidence of association for all available SNPs in a group of related genes, these approaches will have enhanced power to detect genetic associations with complex traits. We performed GSA using data from a genome-wide study of 1165 alcohol-dependent cases and 1379 controls from the Study of Addiction: Genetics and Environment (SAGE), for all 200 pathways listed in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Results demonstrated a potential role of the ‘synthesis and degradation of ketone bodies’ pathway. Our results also support the potential involvement of the ‘neuroactive ligand–receptor interaction’ pathway, which has previously been implicated in addictive disorders. These findings demonstrate the utility of GSA in the study of complex disease, and suggest specific directions for further research into the genetic architecture of alcohol dependence.

scholarly journals Examining the epigenetic mechanisms of childhood adversity and sensitive periods: a gene set-based approach

2021 ◽  
Author(s):  
Yiwen Zhu ◽  
Alexandre A Lussier ◽  
Andrew D.A.C. Smith ◽  
Andrew J. Simpkin ◽  
Matthew J. Suderman ◽  
...  
Keyword(s):  
Middle Childhood ◽  
Developmental Plasticity ◽  
Childhood Adversity ◽  
Sensitivity Analyses ◽  
Sensitive Period ◽  
Epigenetic Mechanisms ◽  
Early Life Adversity ◽  
Linear Discriminant ◽  
Gene Set ◽  
Sensitive Periods

Background: Sensitive periods are developmental stages of heightened plasticity when exposure to childhood adversity may exert lasting impacts. A few biological pathways are known to play key roles in regulating sensitive period plasticity across brain development. Epigenetic mechanisms including DNA methylation (DNAm) may provide a means through which life experiences during sensitive periods induce long-term biological changes. In the current study, we investigated the possibility that adversity during sensitive periods led to DNAm changes in genes that regulate the timing and duration of sensitive periods in development. Methods: Using childhood adversity data and genome-wide DNAm profiles from the Avon Longitudinal Study of Parents and Children (n=785), we summarized DNAm variation of CpG sites in the promoters of genes regulating sensitive periods with the first two principal components (PCs). DNAm summaries were calculated for genes regulating sensitive period opening (ngenes=15), closing (ngenes=36), and expression/duration (ngenes=8). We then performed linear discriminant analysis to test associations between these DNAm summaries and the timing of exposure to seven types of adversity. Results: Sexual or physical abuse and financial hardship during middle childhood (6-7 years) were associated with DNAm of genes regulating the onset and duration of sensitive periods. Sensitivity analyses assessing the presence of any exposure before age 7 and a composite measure of adversity yielded fewer signals, highlighting the importance of accounting for timing and adversity type. Conclusions: With our novel gene set-based approach, we have uncovered suggestive evidence that epigenetic regulation of developmental plasticity may be affected by early life adversity. The complementarity of our gene-level view of the epigenome to the more common and granular epigenome-wide association study may yield novel mechanistic insights not only for adversity but also for other exposures and outcomes.

scholarly journals XRCC5 as a Risk Gene for Alcohol Dependence: Evidence from a Genome-Wide Gene-Set-Based Analysis and Follow-up Studies in Drosophila and Humans

2014 ◽  
Vol 40 (2) ◽  
pp. 361-371 ◽  
Author(s):  
Dilafruz Juraeva ◽  
Jens Treutlein ◽  
Henrike Scholz ◽  
Josef Frank ◽  
Franziska Degenhardt ◽  
...  
Keyword(s):  
Alcohol Dependence ◽  
Gene Set ◽  
Risk Gene ◽  
Genome Wide ◽  
A Genome ◽  
Follow Up Studies

Establishment of a genome-wide RNAi screen; Identification of novel genes involved in clonal maintenance of ALL

2014 ◽  
Vol 226 (03) ◽  
Author(s):  
F Ponthan ◽  
D Pal ◽  
J Vormoor ◽  
O Heidenreich
Keyword(s):  
Rnai Screen ◽  
Novel Genes ◽  
Genome Wide ◽  
A Genome

A genome-wide linkage scan for familial partial lipodystrophy susceptibility genes in a German kindreds

2007 ◽  
Vol 30 (4) ◽  
pp. 86
Author(s):  
M. Lanktree ◽  
J. Robinson ◽  
J. Creider ◽  
H. Cao ◽  
D. Carter ◽  
...  
Keyword(s):  
Subcutaneous Fat ◽  
Visceral Obesity ◽  
Fat Distribution ◽  
Dominant Negative ◽  
Molecular Forms ◽  
Partial Lipodystrophy ◽  
Genome Wide ◽  
A Genome ◽  
Familial Partial Lipodystrophy ◽  
Promoter Mutations

Background: In Dunnigan-type familial partial lipodystrophy (FPLD) patients are born with normal fat distribution, but subcutaneous fat from extremities and gluteal regions are lost during puberty. The abnormal fat distribution leads to the development of metabolic syndrome (MetS), a cluster of phenotypes including hyperglycemia, dyslipidemia, hypertension, and visceral obesity. The study of FPLD as a monogenic model of MetS may uncover genetic risk factors of the common MetS which affects ~30% of adult North Americans. Two molecular forms of FPLD have been identified including FPLD2, resulting from heterozygous mutations in the LMNA gene, and FPLD3, resulting from both heterozygous dominant negative and haploinsufficiency mutations in the PPARG gene. However, many patients with clinically diagnosed FPLD have no mutation in either LMNA or PPARG, suggesting the involvement of additional genes in FPLD etiology. Methods: Here, we report the results of an Affymetrix 10K GeneChip microarray genome-wide linkage analysis study of a German kindred displaying the FPLD phenotype and no known lipodystrophy-causing mutations. Results: The investigation identified three chromosomal loci, namely 1q, 3p, and 9q, with non-parametric logarithm of odds (NPL) scores >2.7. While not meeting the criteria for genome-wide significance, it is interesting to note that the 1q and 3p peaks contain the LMNA and PPARG genes respectively. Conclusions: Three possible conclusions can be drawn from these results: 1) the peaks identified are spurious findings, 2) additional genes physically close to LMNA, PPARG, or within 9q, are involved in FPLD etiology, or 3) alternative disease causing mechanisms not identified by standard exon sequencing approaches, such as promoter mutations, alternative splicing, or epigenetics, are also responsible for FPLD.

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