scholarly journals Natural selection drives genome‐wide evolution via chance genetic associations

2021 ◽  
Author(s):  
Zachariah Gompert ◽  
Jeffrey L. Feder ◽  
Patrik Nosil
Keyword(s):  
Natural Selection ◽  
Genetic Associations ◽  
Genome Wide

scholarly journals Natural selection drives genome-wide evolution via chance genetic associations

2021 ◽  
Author(s):  
Zachariah Gompert ◽  
Jeffrey Feder ◽  
Patrik Nosil
Keyword(s):  
Natural Selection ◽  
Field Experiments ◽  
Indirect Selection ◽  
Direct Selection ◽  
Deer Mice ◽  
Major Theme ◽  
Genetic Associations ◽  
Genome Wide ◽  
Stick Insects ◽  
Causal Variants

Abstract Understanding selection's impact on the genome is a major theme in biology. Functionally-neutral genetic regions can be affected indirectly by natural selection, via their statistical association with genes under direct selection. The genomic extent of such indirect selection, particularly across loci not physically linked to those under direct selection, remains poorly understood, as does the time scale at which indirect selection occurs. Here we use field experiments and genomic data to show that widespread statistical associations with genes known to affect fitness in stick insects, deer mice and stickleback fish cause many genetic loci across the genome to be impacted indirectly by selection. We then show that statistical associations with other, unknown causal variants make aspects of evolution more predictable in stick insects. Thus, natural selection combines with chance genetic associations to affect genome-wide evolution across linked and unlinked loci and even in modest-sized populations.

scholarly journals Genome-Wide Analysis of Sex Disparities in the Genetic Architecture of Lung and Colorectal Cancers

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 686
Author(s):  
Alireza Nazarian ◽  
Alexander M. Kulminski
Keyword(s):  
Nucleotide Polymorphisms ◽  
Genetic Associations ◽  
Significance Level ◽  
Association Analyses ◽  
Complex Disorders ◽  
Specific Effects ◽  
Genome Wide ◽  
Genetic Mechanisms ◽  
Sex Disparities ◽  
Almost All

Almost all complex disorders have manifested epidemiological and clinical sex disparities which might partially arise from sex-specific genetic mechanisms. Addressing such differences can be important from a precision medicine perspective which aims to make medical interventions more personalized and effective. We investigated sex-specific genetic associations with colorectal (CRCa) and lung (LCa) cancers using genome-wide single-nucleotide polymorphisms (SNPs) data from three independent datasets. The genome-wide association analyses revealed that 33 SNPs were associated with CRCa/LCa at P < 5.0 × 10−6 neither males or females. Of these, 26 SNPs had sex-specific effects as their effect sizes were statistically different between the two sexes at a Bonferroni-adjusted significance level of 0.0015. None had proxy SNPs within their ±1 Mb regions and the closest genes to 32 SNPs were not previously associated with the corresponding cancers. The pathway enrichment analyses demonstrated the associations of 35 pathways with CRCa or LCa which were mostly implicated in immune system responses, cell cycle, and chromosome stability. The significant pathways were mostly enriched in either males or females. Our findings provided novel insights into the potential sex-specific genetic heterogeneity of CRCa and LCa at SNP and pathway levels.

scholarly journals Genome-wide association analysis of metabolic syndrome quantitative traits in the GENNID multiethnic family study

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Jia Y. Wan ◽  
Deborah L. Goodman ◽  
Emileigh L. Willems ◽  
Alexis R. Freedland ◽  
Trina M. Norden-Krichmar ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Metabolic Syndrome ◽  
Family Study ◽  
Genome Wide Association ◽  
European American ◽  
Japanese American ◽  
Genetic Associations ◽  
Chromosome 11 ◽  
Genome Wide ◽  
American Families

Abstract Background To identify genetic associations of quantitative metabolic syndrome (MetS) traits and characterize heterogeneity across ethnic groups. Methods Data was collected from GENetics of Noninsulin dependent Diabetes Mellitus (GENNID), a multiethnic resource of Type 2 diabetic families and included 1520 subjects in 259 African-American, European-American, Japanese-Americans, and Mexican-American families. We focused on eight MetS traits: weight, waist circumference, systolic and diastolic blood pressure, high-density lipoprotein, triglycerides, fasting glucose, and insulin. Using genotyped and imputed data from Illumina’s Multiethnic array, we conducted genome-wide association analyses with linear mixed models for all ethnicities, except for the smaller Japanese-American group, where we used additive genetic models with gene-dropping. Results Findings included ethnic-specific genetic associations and heterogeneity across ethnicities. Most significant associations were outside our candidate linkage regions and were coincident within a gene or intergenic region, with two exceptions in European-American families: (a) within previously identified linkage region on chromosome 2, two significant GLI2-TFCP2L1 associations with weight, and (b) one chromosome 11 variant near CADM1-LINC00900 with pleiotropic blood pressure effects. Conclusions This multiethnic family study found genetic heterogeneity and coincident associations (with one case of pleiotropy), highlighting the importance of including diverse populations in genetic research and illustrating the complex genetic architecture underlying MetS.

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 Detecting Genetic Associations betweenATG5and Lupus Nephritis bytrans-eQTL

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Yue-miao Zhang ◽  
Fa-juan Cheng ◽  
Xu-jie Zhou ◽  
Yuan-yuan Qi ◽  
Ping Hou ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Clinical Information ◽  
Nucleotide Polymorphisms ◽  
Genetic Associations ◽  
Single Nucleotide ◽  
Genetic Studies ◽  
Genome Wide ◽  
Custom Made ◽  
Regulatory Effects

Objectives. Numerous loci were identified to perturb gene expression intrans. As elevatedATG5expression was observed in systemic lupus erythematosus (SLE), the study was conducted to analyze the genome-wide genetic regulatory mechanisms associated withATG5expression in a Chinese population with lupus nephritis (LN).Methods. The online expression quantitative trait loci database was searched fortrans-expression single nucleotide polymorphisms (trans-eSNPs) ofATG5. Taggingtrans-eSNPs were genotyped by a custom-made genotyping chip in 280 patients and 199 controls. For positive findings, clinical information and bioinformation analyses were performed.Results. Fourtrans-eSNPs were observed to be associated with susceptibility to LN (P< 0.05), including ANKRD50 rs17008504, AGA rs2271100, PAK7 rs6056923, and TET2 rs1391441, while seven othertrans-eSNPs showed marginal significant associations (0.05 <P< 0.1). Correlations between thetrans-eSNPs andATG5expression and different expression levels ofATG5in SLE patients and controls were validated, and their regulatory effects were annotated. However, no significant associations were observed between different genotypes oftrans-eSNPs and severity or outcome of the patients.Conclusion. Using the new systemic genetics approach, we identified 10 loci associated with susceptibility to LN potentially, which may be complementary to future pathway based genetic studies.

A Proteome-Wide Association Study Identified Candidate Human Brain Proteins Associated with Coffee Consumption

2021 ◽  
Author(s):  
Chun'e Li ◽  
Xiao Liang ◽  
Yumeng Jia ◽  
Yan Wen ◽  
Huijie Zhang ◽  
...  
Keyword(s):  
Human Brain ◽  
Association Study ◽  
Plasma Proteins ◽  
Genome Wide Association Study ◽  
Genetic Correlations ◽  
Coffee Consumption ◽  
Genetic Associations ◽  
Brain Proteins ◽  
Genome Wide ◽  
Brain Proteome

Abstract Background Increasing evidence suggests the association between caffeine and the brain and nervous system. However, there is limited research on the genetic associations between coffee consumption subtypes and brain proteome, plasma proteomes, and peripheral metabolites. Methods First, proteome-wide association study (PWAS) of coffee consumption subtypes was performed by integrating two independent genome-wide association study (GWAS) datasets (91,462–502,650 subjects) with two reference human brain proteomes (ROS/MAP and Banner), by using the FUSION pipeline. Second, transcriptome-wide association study (TWAS) analysis of coffee consumption subtypes was conducted by integrating the two gene expression weight references (RNAseq and splicing) of brain RNA-seq and the two GWAS datasets (91,462–502,650 subjects) of coffee consumption subtypes. Finally, we used the LD Score Regression (LDSC) analysis to evaluate the genetic correlations of coffee consumption subtypes with plasma proteomes and peripheral metabolites. Results For the traits related to coffee consumption, we identified 3 common PWAS proteins, such as MADD (P PWAS−Banner−dis=0.0114, P PWAS−ROS/MAP−rep =0.0489). In addition, 11 common TWAS genes were found in two cohorts, such as ARPC2 (P TWAS−splicing−dis =2063×10− 12, P TWAS−splicing−dis =1.25×10− 10, P TWAS−splicing−dis =1.24e-08, P TWAS−splicing−rep =3.25×10− 9 and P TWAS−splicing−rep =3.42×10− 13). Importantly, we have identified 8 common genes between PWAS and TWAS, such as ALDH2 (P PWAS−banner−rep =1.22×10− 22, PTWAS− splicing−dis = 4.54×10− 92). For the LDSC analysis of human plasma proteome, we identified 11 plasma proteins, such as CHL1 (P dis = 0.0151, P rep =0.0438). For the LDSC analysis of blood metabolites, 5 metabolites have been found, such as myo-inositol (P dis = 0.0073, P dis = 0.0152, P dis =0.0414, P rep =0.0216). Conclusions We identified several brain proteins and genes associated with coffee consumption subtypes. In addition, we also detected several candidate plasma proteins and metabolites related to these subtypes.

scholarly journals Kleine-Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci

2021 ◽  
Vol 118 (12) ◽  
pp. e2005753118
Author(s):  
Aditya Ambati ◽  
Ryan Hillary ◽  
Smaranda Leu-Semenescu ◽  
Hanna M. Ollila ◽  
Ling Lin ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Genome Wide Association Study ◽  
Perinatal Outcomes ◽  
Case Control ◽  
Risk Scores ◽  
Circadian Regulation ◽  
Genetic Associations ◽  
Imaging Studies ◽  
Genome Wide

Kleine-Levin syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case−control genome-wide association study in 673 KLS cases collected over 14 y, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (rs71947865, Odds Ratio [OR] = 1.48, P = 8.6 × 10−9) within the 3′region of TRANK1 gene locus, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 y, we further stratified our sample by birth years and found that recent cases had a significantly reduced rs71947865 association. While the rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR = 1.54, P = 0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo R2 = 0.15; P < 2.0 × 10−22 at P = 0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, circadian regulation, and bipolar disorder, and indicate that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.

scholarly journals Genetic Determinants of Telomere Length in African American Youth

2018 ◽  
Author(s):  
Andrew M. Zeiger ◽  
Marquitta J. White ◽  
Sam S. Oh ◽  
Jonathan Witonsky ◽  
Maria G. Contreras ◽  
...  
Keyword(s):  
African American ◽  
Telomere Length ◽  
Genome Wide Association Study ◽  
African Ancestry ◽  
African American Youth ◽  
Genetic Associations ◽  
Disease States ◽  
Genome Wide ◽  
Pediatric Populations ◽  
Genetic And Environmental Factors

ABSTRACTTelomere length (TL) is associated with numerous disease states and is affected by genetic and environmental factors. However, TL has been mostly studied in adult populations of European or Asian ancestry. These studies have identified 34 TL-associated genetic variants recently used as genetic proxies for TL. The generalizability of these associations to pediatric populations and racially diverse populations, specifically of African ancestry, remains unclear. Furthermore, six novel variants associated with TL in a population of European children have been identified but not validated. We measured TL from whole blood samples of 492 healthy African American youth (children and adolescents between 8 and 20 years old) and performed the first genome-wide association study of TL in this population. We were unable to replicate neither the 34 reported genetic associations found in adults nor the six genetic associations found in European children. However, we discovered a novel genome-wide significant association between TL and rs1483898 on chromosome 14. Our results underscore the importance of examining these genetic associations with TL in diverse pediatric populations such as African Americans.

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