scholarly journals GWAS Meta-Analysis of Neuroticism (N=449,484) Identifies Novel Genetic Loci and Pathways

2017 ◽  
Author(s):  
Mats Nagel ◽  
Philip R Jansen ◽  
Sven Stringer ◽  
Kyoko Watanabe ◽  
Christiaan A de Leeuw ◽  
...  
Keyword(s):  
Association Studies ◽  
Meta Analysis ◽  
Cell Types ◽  
Brain Regions ◽  
Specific Cell ◽  
Medium Spiny Neurons ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Genetic Signal

Neuroticism is an important risk factor for psychiatric traits including depression1, anxiety2,3, and schizophrenia4–6. Previous genome-wide association studies7–12 (GWAS) reported 16 genomic loci10–12. Here we report the largest neuroticism GWAS meta-analysis to date (N=449,484), and identify 136 independent genome-wide significant loci (124 novel), implicating 599 genes. Extensive functional follow-up analyses show enrichment in several brain regions and involvement of specific cell-types, including dopaminergic neuroblasts (P=3×10-8), medium spiny neurons (P=4×10-8) and serotonergic neurons (P=1×10-7). Gene-set analyses implicate three specific pathways: neurogenesis (P=4.4×10-9), behavioural response to cocaine processes (P=1.84×10-7), and axon part (P=5.26×10-8). We show that neuroticism’s genetic signal partly originates in two genetically distinguishable subclusters13 (depressed affect and worry, the former being genetically strongly related to depression, rg=0.84), suggesting distinct causal mechanisms for subtypes of individuals. These results vastly enhance our neurobiological understanding of neuroticism, and provide specific leads for functional follow-up experiments.

scholarly journals Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions

2018 ◽  
Author(s):  
David M. Howard ◽  
Mark J. Adams ◽  
Toni-Kim Clarke ◽  
Jonathan D. Hafferty ◽  
Jude Gibson ◽  
...  
Keyword(s):  
Multiple Testing ◽  
Drug Repositioning ◽  
Association Studies ◽  
Meta Analysis ◽  
Enrichment Analysis ◽  
Brain Regions ◽  
Genome Wide Association Studies ◽  
Multiple Testing Correction ◽  
Synaptic Structure ◽  
Genome Wide

AbstractMajor depression is a debilitating psychiatric illness that is typically associated with low mood, anhedonia and a range of comorbidities. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximise sample size, we meta-analysed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 gene-sets associated with depression, including both genes and gene-pathways associated with synaptic structure and neurotransmission. Further evidence of the importance of prefrontal brain regions in depression was provided by an enrichment analysis. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant following multiple testing correction. Based on the putative genes associated with depression this work also highlights several potential drug repositioning opportunities. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding aetiology and developing new treatment approaches.

scholarly journals Discovery and prioritization of variants and genes for kidney function in >1.2 million individuals

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Kira J. Stanzick ◽  
Yong Li ◽  
Pascal Schlosser ◽  
Mathias Gorski ◽  
Matthias Wuttke ◽  
...  
Keyword(s):  
Kidney Function ◽  
Fine Mapping ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association Studies ◽  
Functional Studies ◽  
Genome Wide ◽  
Credible Sets ◽  
Variance Explained

AbstractGenes underneath signals from genome-wide association studies (GWAS) for kidney function are promising targets for functional studies, but prioritizing variants and genes is challenging. By GWAS meta-analysis for creatinine-based estimated glomerular filtration rate (eGFR) from the Chronic Kidney Disease Genetics Consortium and UK Biobank (n = 1,201,909), we expand the number of eGFRcrea loci (424 loci, 201 novel; 9.8% eGFRcrea variance explained by 634 independent signal variants). Our increased sample size in fine-mapping (n = 1,004,040, European) more than doubles the number of signals with resolved fine-mapping (99% credible sets down to 1 variant for 44 signals, ≤5 variants for 138 signals). Cystatin-based eGFR and/or blood urea nitrogen association support 348 loci (n = 460,826 and 852,678, respectively). Our customizable tool for Gene PrioritiSation reveals 23 compelling genes including mechanistic insights and enables navigation through genes and variants likely relevant for kidney function in human to help select targets for experimental follow-up.

scholarly journals Differential and spatial expression meta-analysis of genes identified in genome-wide association studies of depression

2020 ◽  
Author(s):  
Wennie Wu ◽  
Derek Howard ◽  
Etienne Sibille ◽  
Leon French
Keyword(s):  
Differential Expression ◽  
Association Studies ◽  
Meta Analysis ◽  
Cell Types ◽  
Brain Regions ◽  
Enteric Neurons ◽  
Dorsal Lateral Geniculate Nucleus ◽  
Genome Wide Association Studies ◽  
Specific Effects ◽  
Dorsal Lateral Geniculate

AbstractMajor depressive disorder (MDD) is the most prevalent psychiatric disorder worldwide and affects individuals of all ages. It causes significant psychosocial impairments and is a major cause of disability. A recent consortium study identified 102 genetic variants and 269 genes associated with depression. To provide targets for future depression research, we prioritized these recently identified genes using expression data. We examined differential expression of these genes in three studies that profiled gene expression of MDD cases and controls across multiple brain regions. In addition, we integrated anatomical expression information to determine which brain regions and transcriptomic cell-types highly express the candidate genes. We highlight 11 of the 269 genes with the most consistent differential expression: MANEA, UBE2M, CKB, ITPR3, SPRY2, SAMD5, TMEM106B, ZC3H7B, LST1, ASXL3 and HSPA1A. The majority of these top genes were found to have sex-specific differential expression. We place greater emphasis on MANEA as it is the top gene in a more conservative analysis of the 269. Specifically, differential expression of MANEA was strongest in cerebral cortex regions and had opposing sex-specific effects. Anatomically, our results suggest the importance of the dorsal lateral geniculate nucleus, cholinergic, monoaminergic, and enteric neurons. These findings provide a guide for targeted experiments to advance our understanding of the genetic underpinnings of depression.

Abstract 33: A Meta-analysis Of Three Genome-wide Association Studies Identifies A Novel Susceptibility Locus For Kawasaki Disease.

Circulation ◽  
2015 ◽  
Vol 131 (suppl_2) ◽  
Author(s):  
Todd A Johnson ◽  
Jer-Yuarn Wu ◽  
Dankyu Yoon ◽  
Akira Hata ◽  
Michiaki Kubo ◽  
...  
Keyword(s):  
Kawasaki Disease ◽  
Association Studies ◽  
Meta Analysis ◽  
East Asian ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Asian Populations ◽  
Genome Wide ◽  
Follow Up Studies

Background: Although genome-wide association studies (GWAS) have conclusively identified several susceptibility genes / loci for Kawasaki disease (KD), a large part of the genetic etiology of this disease have not been unraveled and, above all, its marked predilection for East Asian populations have not been explained. Objective: To identify genetic variants commonly associated with KD in the East Asian populations, we conducted a meta-analysis of three GWASes from Japan, Korea and Taiwan. Methods: In the GWAS analyses, we genotyped 6322 subjects (1236 cases and 5086 controls) using either Illumina 550K or Affymetrix SNP 6.0 platforms and then imputed untyped genotypes using Impute2 or minimac software with 1000 Genomes Project’s East Asian population (JPT, CHB and CHS) reference haplotype data. We then performed a meta-analysis using a weighted-average method with inverse-variance weights and selected representative SNPs in 49 top associated loci, which were then genotyped in 4798 independent subjects (2151 cases and 2747 controls). Finally, we combined the data for the three GWASes and follow up studies in a meta-analysis. Results: SNPs within previously identified susceptibility loci showed significant association in the meta-analysis of the GWASes (ITPKC: rs28493229, P = 3.07 x 10-9; CASP3: rs2720377, P = 2.66 x 10-9; BLK: rs2736340, P = 1.23 x 10-16; CD40: rs1883832, P = 1.76 x 10-8; HLA class2: rs189914842, P = 4.57 x 10-11). In a meta-analysis of the three GWASes and follow-up studies, we observed a genome-wide significant level of association at a SNP in a chromosomal region different from the six known loci (P = 6.49 x 10-9). Conclusion: The meta-analysis of three GWAses and follow-up studies successfully identified a new SNP significantly associated with KD. Further investigation of the region where the SNP is located toward specification of the susceptibility gene, the responsible variant, as well as its effect on gene function is warranted. Acknowledgement: T.A.J., J.Y.W. and D.Y. equally contributed to this work and J.K.L., Y.T.C., and Y.O. are co-directing this project.

scholarly journals Differential and spatial expression meta-analysis of genes identified in genome-wide association studies of depression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Wennie Wu ◽  
Derek Howard ◽  
Etienne Sibille ◽  
Leon French
Keyword(s):  
Differential Expression ◽  
Association Studies ◽  
Meta Analysis ◽  
Cell Types ◽  
Brain Regions ◽  
Enteric Neurons ◽  
Dorsal Lateral Geniculate Nucleus ◽  
Genome Wide Association Studies ◽  
Subcortical Regions ◽  
Dorsal Lateral Geniculate

AbstractMajor depressive disorder (MDD) is the most prevalent psychiatric disorder worldwide and affects individuals of all ages. It causes significant psychosocial impairments and is a major cause of disability. A recent consortium study identified 102 genetic variants and 269 genes associated with depression. To provide targets for future depression research, we prioritized these recently identified genes using expression data. We examined the differential expression of these genes in three studies that profiled gene expression of MDD cases and controls across multiple brain regions. In addition, we integrated anatomical expression information to determine which brain regions and transcriptomic cell types highly express the candidate genes. We highlight 12 of the 269 genes with the most consistent differential expression: MANEA, UBE2M, CKB, ITPR3, SPRY2, SAMD5, TMEM106B, ZC3H7B, LST1, ASXL3, ZNF184 and HSPA1A. The majority of these top genes were found to have sex-specific differential expression. We place greater emphasis on ZNF184 as it is the top gene in a more conservative analysis of the 269. Specifically, the differential expression of ZNF184 was strongest in subcortical regions in males and females. Anatomically, our results suggest the importance of the dorsal lateral geniculate nucleus, cholinergic, monoaminergic and enteric neurons. These findings provide a guide for targeted experiments to advance our understanding of the genetic underpinnings of depression.

Genome-Wide Association Studies Identify Two Novel Loci Conferring Susceptibility to Diabetic Retinopathy in Japanese Patients with Type 2 Diabetes

2021 ◽  
Author(s):  
Minako Imamura ◽  
Atsushi Takahashi ◽  
Masatoshi Matsunami ◽  
Momoko Horikoshi ◽  
Minoru Iwata ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Retinopathy ◽  
Association Studies ◽  
Meta Analysis ◽  
Japanese Patients ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Stage 1

Abstract Several reports have suggested that genetic susceptibility contributes to the development and progression of diabetic retinopathy. We aimed to identify genetic loci that confer susceptibility to diabetic retinopathy in Japanese patients with type 2 diabetes. We analysed 5 790 508 single nucleotide polymorphisms (SNPs) in 8880 Japanese patients with type 2 diabetes, 4839 retinopathy cases and 4041 controls, as well as 2217 independent Japanese patients with type 2 diabetes, 693 retinopathy cases, and 1524 controls. The results of these two genome-wide association studies (GWAS) were combined with an inverse variance meta-analysis (Stage-1), followed by de novo genotyping for the candidate SNP loci (p < 1.0 × 10−4) in an independent case–control study (Stage-2, 2260 cases and 723 controls). After combining the association data (Stage-1 and -2) using meta-analysis, the associations of two loci reached a genome-wide significance level: rs12630354 near STT3B on chromosome 3, p = 1.62 × 10−9, odds ratio (OR) = 1.17, 95% confidence interval (CI) 1.11–1.23, and rs140508424 within PALM2 on chromosome 9, p = 4.19 × 10−8, OR = 1.61, 95% CI 1.36–1.91. However, the association of these two loci were not replicated in Korean, European, or African American populations. Gene-based analysis using Stage-1 GWAS data identified a gene-level association of EHD3 with susceptibility to diabetic retinopathy (p = 2.17 × 10−6). In conclusion, we identified two novel SNP loci, STT3B and PALM2, and a novel gene, EHD3, that confers susceptibility to diabetic retinopathy; however, further replication studies are required to validate these associations.

scholarly journals A meta-analysis of genome-wide association studies for average daily gain and lean meat percentage in two Duroc pig populations

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Shenping Zhou ◽  
Rongrong Ding ◽  
Fanming Meng ◽  
Xingwang Wang ◽  
Zhanwei Zhuang ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Growth And Development ◽  
Genetic Architecture ◽  
Association Studies ◽  
Meta Analysis ◽  
Average Daily Gain ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Daily Gain

Abstract Background Average daily gain (ADG) and lean meat percentage (LMP) are the main production performance indicators of pigs. Nevertheless, the genetic architecture of ADG and LMP is still elusive. Here, we conducted genome-wide association studies (GWAS) and meta-analysis for ADG and LMP in 3770 American and 2090 Canadian Duroc pigs. Results In the American Duroc pigs, one novel pleiotropic quantitative trait locus (QTL) on Sus scrofa chromosome 1 (SSC1) was identified to be associated with ADG and LMP, which spans 2.53 Mb (from 159.66 to 162.19 Mb). In the Canadian Duroc pigs, two novel QTLs on SSC1 were detected for LMP, which were situated in 3.86 Mb (from 157.99 to 161.85 Mb) and 555 kb (from 37.63 to 38.19 Mb) regions. The meta-analysis identified ten and 20 additional SNPs for ADG and LMP, respectively. Finally, four genes (PHLPP1, STC1, DYRK1B, and PIK3C2A) were detected to be associated with ADG and/or LMP. Further bioinformatics analysis showed that the candidate genes for ADG are mainly involved in bone growth and development, whereas the candidate genes for LMP mainly participated in adipose tissue and muscle tissue growth and development. Conclusions We performed GWAS and meta-analysis for ADG and LMP based on a large sample size consisting of two Duroc pig populations. One pleiotropic QTL that shared a 2.19 Mb haplotype block from 159.66 to 161.85 Mb on SSC1 was found to affect ADG and LMP in the two Duroc pig populations. Furthermore, the combination of single-population and meta-analysis of GWAS improved the efficiency of detecting additional SNPs for the analyzed traits. Our results provide new insights into the genetic architecture of ADG and LMP traits in pigs. Moreover, some significant SNPs associated with ADG and/or LMP in this study may be useful for marker-assisted selection in pig breeding.

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