scholarly journals A Transcriptome Wide Association Study implicates specific pre- and post-synaptic abnormalities in Schizophrenia

2018 ◽  
Author(s):  
Lynsey S Hall ◽  
Christopher W Medway ◽  
Antonio F Pardinas ◽  
Elliott G Rees ◽  
Valentina Escott-Price ◽  
...  
Keyword(s):  
Association Study ◽  
System Development ◽  
Association Studies ◽  
Experimental Studies ◽  
Long Term Potentiation ◽  
Nervous System Development ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Heritable Disorder

AbstractSchizophrenia is a complex highly heritable disorder. Genome-wide association studies have identified multiple loci that influence the risk of developing schizophrenia, although the causal variants driving these associations and their impacts on specific genes are largely unknown. Here we link genetic findings to gene expression in the human brain by performing a transcriptome-wide association study (TWAS) in which we integrate the largest published genome-wide association dataset of schizophrenia, with publically available post mortem expression data from the dorsolateral prefrontal cortex (DLPFC). We identify a significant correlation between schizophrenia risk and expression at eighty-nine genes in DLPFC, including forty-two genes not identified in earlier TWAS of this transcriptomic resource. Genes whose expression correlate with schizophrenia were enriched for those involved in nervous system development, abnormal synaptic transmission, reduced long term potentiation, and calcium-dependent cell-cell adhesion. Previous genetic studies have implicated post-synaptic glutamatergic and gabaergic processes in schizophrenia; here we extend this to include molecules that regulate presynaptic transmitter release. We identify specific candidate genes to which we assign predicted directions of effect in terms of expression level, facilitating downstream experimental studies geared towards a better mechanistic understanding of schizophrenia pathogenesis.

scholarly journals Joint Genome-Wide Association Study Identifies Twenty-One Novel Loci for Age at Menarche and Highlights Its Causal Association with Other Complex Diseases

2021 ◽  
Author(s):  
Gui-Juan Feng ◽  
Qian Xu ◽  
Jing-Jing Ni ◽  
Shan-Shan Yang ◽  
Bai-Xue Han ◽  
...  
Keyword(s):  
Association Study ◽  
Complex Traits ◽  
Causal Effect ◽  
Association Studies ◽  
Genetic Correlations ◽  
Genome Wide Association ◽  
Age At Menarche ◽  
Luteinizing Hormone Level ◽  
Genome Wide Association Studies ◽  
Genome Wide

Abstract Age at menarche (AAM) is a sign of puberty of females. It is a heritable trait associated with various adult diseases. However, the genetic mechanism that determines AAM and links it to disease risk is poorly understood. Aiming to uncover the genetic basis for AAM, we conducted a joint association study in up to 438,089 participants from 3 genome-wide association studies of European and East Asian ancestries. Twenty-one novel genomic loci were identified at the genome-wide significance level. Besides, we observed significant genetic correlations between AAM and 67 complex traits, and the highest genetic correlation was observed between AAM and body mass index (rg=-0.19, P=6.11×10−31). Latent causal variable analyses demonstrate that there is a genetically causal effect of AAM on high blood pressure (GCP=0.47, P=0.02), forced vital capacity (GCP=0.63, P=0.02), age at first live birth (GCP=0.51, P=0.03), impedance of right arm (GCP=0.41, P<1×10-7) and right leg fat percentage (GCP=-0.10, P=0.02), etc. Enrichment analysis identified 5 enriched tissues and 51 enriched gene sets. Four of the five enriched tissues were related to the nervous system, including the hypothalamus middle, hypothalamo hypophyseal system, neurosecretory systems and hypothalamus. The fifth tissue was the retina in the sensory organ. The most significant gene set was the ‘decreased circulating luteinizing hormone level’ (P=2.45×10-6). Our findings may provide useful insights that elucidate the mechanisms determining AAM and the genetic interplay between AAM and some traits of women.

Replication study of previous migraine genome-wide association study findings in a Spanish sample of migraine with aura

Cephalalgia ◽  
2014 ◽  
Vol 35 (9) ◽  
pp. 776-782 ◽  
Author(s):  
Cèlia Sintas ◽  
Jèssica Fernández-Morales ◽  
Marta Vila-Pueyo ◽  
Bernat Narberhaus ◽  
Concepció Arenas ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Association Study ◽  
Migraine With Aura ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Genome Wide

Background Migraine is a common disabling condition that affects approximately 15% of the population. Several genome-wide association studies have attempted to identify susceptibility variants involved in migraine, reporting several candidate loci for the disorder. Methods In order to replicate findings from previous genome-wide association studies, a case–control association study was performed. Twelve single nucleotide polymorphisms were genotyped in a Spanish sample of 512 migraine with aura patients and 535 migraine-free controls. Results Nominal associations were found for single nucleotide polymorphisms rs2651899 (within the PRDM16 gene), rs10166942 (near TRPM8), rs12134493 (close to TSPAN2) and rs10504861 (near MMP16) in our migraine with aura sample. Conclusions Our study provides suggestive replication, in a Spanish migraine with aura sample, of four genome-wide association study findings previously reported in common migraine. However, larger sample sets should be explored to confirm our results.

scholarly journals Genome-Wide Association Studies Reveal Neurological Genes for Dog Herding, Predation, Temperament, and Trainability Traits

2021 ◽  
Vol 8 ◽  
Author(s):  
Shuwen Shan ◽  
Fangzheng Xu ◽  
Bertram Brenig
Keyword(s):  
Body Size ◽  
Candidate Genes ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Nervous System Development ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Behavioral Traits ◽  
Genome Wide ◽  
Dog Breed

Genome-wide association study (GWAS) using dog breed standard values as phenotypic measurements is an efficient way to identify genes associated with morphological and behavioral traits. As a result of strong human purposeful selections, several specialized behavioral traits such as herding and hunting have been formed in different modern dog breeds. However, genetic analyses on this topic are rather limited due to the accurate phenotyping difficulty for these complex behavioral traits. Here, 268 dog whole-genome sequences from 130 modern breeds were used to investigate candidate genes underlying dog herding, predation, temperament, and trainability by GWAS. Behavioral phenotypes were obtained from the American Kennel Club based on dog breed standard descriptions or groups (conventional categorization of dog historical roles). The GWAS results of herding behavior (without body size as a covariate) revealed 44 significantly associated sites within five chromosomes. Significantly associated sites on CFA7, 9, 10, and 20 were located either in or near neuropathological or neuronal genes including THOC1, ASIC2, MSRB3, LLPH, RFX8, and CHL1. MSRB3 and CHL1 genes were reported to be associated with dog fear. Since herding is a restricted hunting behavior by removing killing instinct, 36 hounds and 55 herding dogs were used to analyze predation behavior. Three neuronal-related genes (JAK2, MEIS1, and LRRTM4) were revealed as candidates for predation behavior. The significantly associated variant of temperament GWAS was located within ACSS3 gene. The highest associated variant in trainability GWAS is located on CFA22, with no variants detected above the Bonferroni threshold. Since dog behaviors are correlated with body size, we next incorporate body mass as covariates into GWAS; and significant signals around THOC1, MSRB3, LLPH, RFX8, CHL1, LRRTM4, and ACSS3 genes were still detected for dog herding, predation, and temperament behaviors. In humans, these candidate genes are either involved in nervous system development or associated with mental disorders. In conclusion, our results imply that these neuronal or psychiatric genes might be involved in biological processes underlying dog herding, predation, and temperament behavioral traits.

scholarly journals The predictive power of the microbiome exceeds that of genome-wide association studies in the discrimination of complex human disease

2020 ◽  
Author(s):  
Braden T Tierney ◽  
Yixuan He ◽  
George M Church ◽  
Eran Segal ◽  
Aleksandar D Kostic ◽  
...  
Keyword(s):  
Association Study ◽  
Human Disease ◽  
Genome Wide Association Study ◽  
Human Genetics ◽  
Association Studies ◽  
Human Microbiome ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Common Variants ◽  
Genome Wide

AbstractOver the past decade, studies of the human genome and microbiome have deepened our understanding of the connections between human genes, environments, microbes, and disease. For example, the sheer number of indicators of the microbiome and human genetic common variants associated with disease has been immense, but clinical utility has been elusive. Here, we compared the predictive capabilities of the human microbiome versus human genomic common variants across 13 common diseases. We concluded that microbiomic indicators outperform human genetics in predicting host phenotype (overall Microbiome-Association-Study [MAS] area under the curve [AUC] = 0.79 [SE = 0.03], overall Genome-Wide-Association-Study [GWAS] AUC = 0.67 [SE = 0.02]). Our results, while preliminary and focused on a subset of the totality of disease, demonstrate the relative predictive ability of the microbiome, indicating that it may outperform human genetics in discriminating human disease cases and controls. They additionally motivate the need for population-level microbiome sequencing resources, akin to the UK Biobank, to further improve and reproduce metagenomic models of disease.

scholarly journals A Transcriptome-Wide Association Study Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer

2020 ◽  
Vol 112 (10) ◽  
pp. 1003-1012 ◽  
Author(s):  
Jun Zhong ◽  
Ashley Jermusyk ◽  
Lang Wu ◽  
Jason W Hoskins ◽  
Irene Collins ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pancreatic Cancer ◽  
Cancer Risk ◽  
Association Study ◽  
Association Studies ◽  
Tissue Expression ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Pancreatic Cancer Risk ◽  
Genome Wide

Abstract Background Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. Methods To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74–421 samples). Results We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate &lt; .05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at six known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction. Conclusions By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.

scholarly journals Association study of childhood obesity with eight genetic variants recently identified by genome-wide association studies

2014 ◽  
Vol 76 (3) ◽  
pp. 310-315 ◽  
Author(s):  
Xiang-Rui Meng ◽  
Jie-Yun Song ◽  
Jun Ma ◽  
Fang-Hong Liu ◽  
Xiao-Rui Shang ◽  
...  
Keyword(s):  
Childhood Obesity ◽  
Association Study ◽  
Genetic Variants ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

scholarly journals Multiple Testing in the Context of Gene Discovery in Sickle Cell Disease Using Genome-Wide Association Studies

2017 ◽  
Vol 10 ◽  
pp. 117863101772117 ◽  
Author(s):  
Kevin H.M. Kuo
Keyword(s):  
Sickle Cell Disease ◽  
Association Study ◽  
Sickle Cell ◽  
Multiple Testing ◽  
Association Studies ◽  
Gene Discovery ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Cell Disease ◽  
Genome Wide

The issue of multiple testing, also termed multiplicity, is ubiquitous in studies where multiple hypotheses are tested simultaneously. Genome-wide association study (GWAS), a type of genetic association study that has gained popularity in the past decade, is most susceptible to the issue of multiple testing. Different methodologies have been employed to address the issue of multiple testing in GWAS. The purpose of the review is to examine the methodologies employed in dealing with multiple testing in the context of gene discovery using GWAS in sickle cell disease complications.

scholarly journals VAMPIRE: A model blood cell trait focused annotation tool for interpretation and prioritization of complex trait genome-wide association study results

2021 ◽  
Author(s):  
Cheynna Crowley ◽  
Quan Sun ◽  
Le Huang ◽  
Erik L. Bao ◽  
Paul Auer ◽  
...  
Keyword(s):  
Blood Cell ◽  
Association Study ◽  
Complex Traits ◽  
Web Application ◽  
Target Genes ◽  
Association Studies ◽  
Complex Trait ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

AbstractThousands of genetic loci have been identified as associated with hematological indices (red blood cell, white blood cell, and platelet related traits), as well as other complex traits and disease. However, most loci identified are noncoding and not clearly linked to target genes, and tools are needed to prioritize the most likely functional variants for experimental follow-up. We here describe VAMPIRE: Variant Annotation Method Pointing to Interesting Regulatory Effects, an interactive web application implemented in R Shiny (http://shiny.bios.unc.edu/vampire/) for blood cell trait associated loci from recent large multi-ethnic genome-wide association studies (GWAS). This tool efficiently displays information from blood cell relevant tissues on epigenomic signatures, functional and conservation summary scores, variant impact on protein and gene expression, chromatin conformation information from Hi-C and similar technologies, as well as publicly available GWAS and phenome-wide association study (PheWAS) results. Variants are classified into multiple prioritization categories according to these functional signatures. Leveraging data generated from independent functional validation experiments, we demonstrate that our prioritized variants are enriched within experimentally validated variant sets. VAMPIRE allows rapid prioritization and interpretation of blood cell trait GWAS variants and could be easily adapted for use with other complex trait GWAS results and extended to new annotation sources.Author SummaryMany large genome-wide association studies (GWAS) have recently been performed for blood cell traits, with thousands of associations identified. However, most of the associated variants are in noncoding regions and are often hard to interpret, link to genes, and prioritize for functional follow-up. Similar challenges exist for genetic studies of many other traits and diseases. Trying to translate knowledge of GWAS significant variants to target genes and biological insights, we here describe VAMPIRE: Variant Annotation Method Pointing to Interesting Regulatory Effects, an interactive web application implemented in R Shiny (http://shiny.bios.unc.edu/vampire/) for blood cell trait associated loci from recent large multi-ethnic GWAS. This tool displays a variety of information including epigenomic signatures, variant impact on protein and gene expression, chromatin conformation information, and publicly available GWAS and phenome-wide association study (PheWAS) results for other traits. We classified variants into annotation categories using this information, and show that variants in the highest priority categories are enriched in likely causal variant sets from previous functional experiments. We anticipate this tool will guide appropriate variants to prioritize for experimental validation for researchers studying blood cell traits, as well as providing an easily adaptable model for the creation of similar annotation tools for other complex traits and diseases.

Sign in / Sign up

Export Citation Format

Share Document