Analysis of Major Depression Risk Genes Reveals Evolutionary Conservation, Shared Phenotypes, and Extensive Genetic Interactions

Major depressive disorder (MDD) affects around 15% of the population at some stage in their lifetime. It can be gravely disabling and it is associated with increased risk of suicide. Genetics play an important role; however, there are additional environmental contributions to the pathogenesis. A number of possible risk genes that increase liability for developing symptoms of MDD have been identified in genome-wide association studies (GWAS). The goal of this study was to characterize the MDD risk genes with respect to the degree of evolutionary conservation in simpler model organisms such as Caenorhabditis elegans and zebrafish, the phenotypes associated with variation in these genes and the extent of network connectivity. The MDD risk genes showed higher conservation in C. elegans and zebrafish than genome-to-genome comparisons. In addition, there were recurring themes among the phenotypes associated with variation of these risk genes in C. elegans. The phenotype analysis revealed enrichment for essential genes with pleiotropic effects. Moreover, the MDD risk genes participated in more interactions with each other than did randomly-selected genes from similar-sized gene sets. Syntenic blocks of risk genes with common functional activities were also identified. By characterizing evolutionarily-conserved counterparts to the MDD risk genes, we have gained new insights into pathogenetic processes relevant to the emergence of depressive symptoms in man.

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Animal Models of GWAS-Identified Type 2 Diabetes Genes

Journal of Diabetes Research ◽

10.1155/2013/906590 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 21

Author(s):

Gabriela da Silva Xavier ◽

Elisa A. Bellomo ◽

James A. McGinty ◽

Paul M. French ◽

Guy A. Rutter

Keyword(s):

Type 2 Diabetes ◽

Animal Models ◽

Mouse Models ◽

Human Genetics ◽

Association Studies ◽

Genome Wide Association Studies ◽

Risk Genes ◽

Genome Wide ◽

Increased Risk

More than 65loci, encoding up to 500 different genes, have been implicated by genome-wide association studies (GWAS) as conferring an increased risk of developing type 2 diabetes (T2D). Whilst mouse models have in the past been central to understanding the mechanisms through which more penetrant risk genes for T2D, for example, those responsible for neonatal or maturity-onset diabetes of the young, only a few of those identified by GWAS, notablyTCF7L2andZnT8/SLC30A8, have to date been examined in mouse models. We discuss here the animal models available for the latter genes and provide perspectives for future, higher throughput approaches towards efficiently mining the information provided by human genetics.

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TLR1 and PRKAA1 Gene Polymorphisms in the Development of Atrophic Gastritis and Gastric Cancer

Journal of Gastrointestinal and Liver Diseases ◽

10.15403/jgld.2014.1121.274.tlr ◽

2018 ◽

Vol 27 (4) ◽

pp. 363-369 ◽

Cited By ~ 4

Author(s):

Gintare Dargiene ◽

Greta Streleckiene ◽

Jurgita Skieceviciene ◽

Marcis Leja ◽

Alexander Link ◽

...

Keyword(s):

Gastric Cancer ◽

Atrophic Gastritis ◽

Genetic Polymorphisms ◽

Association Studies ◽

Control Group ◽

Similar Distribution ◽

Genome Wide Association Studies ◽

Increased Risk ◽

Infection Susceptibility ◽

H Pylori

Background & Aims: Previous genome-wide association studies showed that genetic polymorphisms in toll-like receptor 1 (TLR1) and protein kinase AMP-activated alpha 1 catalytic subunit (PRKAA1) genes were associated with gastric cancer (GC) or increased Helicobacter pylori (H. pylori) infection susceptibility. The aim of this study was to evaluate the association between TLR1 and PRKAA1 genes polymorphisms and H.pylori infection, atrophic gastritis (AG) or GC in the European population.Methods: Single-nucleotide polymorphisms (SNPs) were analysed in 511 controls, 340 AG patients and 327 GC patients. TLR1 C>T (rs4833095) and PRKAA1 C>T (rs13361707) were genotyped by the real-time polymerase chain reaction. H. pylori status was determined by testing for anti-H. pylori IgG antibodies in the serum.Results: The study included 697 (59.2%) H. pylori positive and 481 (40.8%) H. pylori negative cases. We observed similar distribution of TLR1 and PRKAA1 alleles and genotypes in H. pylori positive and negative cases. TLR1 and PRKAA1 SNPs were not linked with the risk of AG. TC genotype of TLR1 gene was more prevalent in GC patients compared to the control group (29.7% and 22.3% respectively, p=0.002). Carriers of TC genotype had a higher risk of GC (aOR=1.89, 95% CI: 1.26–2.83, p=0.002). A similar association was observed in a dominant inheritance model for TLR1 gene SNP, where comparison of CC+TC vs. TT genotypes showed an increased risk of GC (aOR=1.86, 95% CI: 1.26–2.75, p=0.002). No association between genetic polymorphism in PRKAA1 gene and GC was observed.Conclusions: TLR1 rs4833095 SNP was associated with an increased risk of GC in a European population, while PRKAA1 rs13361707 genetic variant was not linked with GC. Both genetic polymorphisms were not associated with H. pylori infection susceptibility or the risk of AG.

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GWAS of serum ALT and AST reveals an association of SLC30A10 Thr95Ile with hypermanganesemia symptoms

Nature Communications ◽

10.1038/s41467-021-24563-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Lucas D. Ward ◽

Ho-Chou Tu ◽

Chelsea B. Quenneville ◽

Shira Tsour ◽

Alexander O. Flynn-Carroll ◽

...

Keyword(s):

Bile Duct ◽

Extrahepatic Bile Duct ◽

Association Studies ◽

Missense Variant ◽

Deficiency Anemia ◽

Genome Wide Association Studies ◽

Loss Of Function ◽

Extrahepatic Bile Duct Cancer ◽

Hepatocellular Damage ◽

Increased Risk

AbstractUnderstanding mechanisms of hepatocellular damage may lead to new treatments for liver disease, and genome-wide association studies (GWAS) of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum activities have proven useful for investigating liver biology. Here we report 100 loci associating with both enzymes, using GWAS across 411,048 subjects in the UK Biobank. The rare missense variant SLC30A10 Thr95Ile (rs188273166) associates with the largest elevation of both enzymes, and this association replicates in the DiscovEHR study. SLC30A10 excretes manganese from the liver to the bile duct, and rare homozygous loss of function causes the syndrome hypermanganesemia with dystonia-1 (HMNDYT1) which involves cirrhosis. Consistent with hematological symptoms of hypermanganesemia, SLC30A10 Thr95Ile carriers have increased hematocrit and risk of iron deficiency anemia. Carriers also have increased risk of extrahepatic bile duct cancer. These results suggest that genetic variation in SLC30A10 adversely affects more individuals than patients with diagnosed HMNDYT1.

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The Genetic Basis of Hypertriglyceridemia

Current Atherosclerosis Reports ◽

10.1007/s11883-021-00939-y ◽

2021 ◽

Vol 23 (8) ◽

Author(s):

Germán D. Carrasquilla ◽

Malene Revsbech Christiansen ◽

Tuomas O. Kilpeläinen

Keyword(s):

Genetic Basis ◽

Association Studies ◽

Cumulative Effect ◽

Genome Wide Association Studies ◽

Genetic Loci ◽

Risk Variants ◽

Genome Wide ◽

Severe Hypertriglyceridemia ◽

Increased Risk ◽

Polygenic Scores

Abstract Purpose of Review Hypertriglyceridemia is a common dyslipidemia associated with an increased risk of cardiovascular disease and pancreatitis. Severe hypertriglyceridemia may sometimes be a monogenic condition. However, in the vast majority of patients, hypertriglyceridemia is due to the cumulative effect of multiple genetic risk variants along with lifestyle factors, medications, and disease conditions that elevate triglyceride levels. In this review, we will summarize recent progress in the understanding of the genetic basis of hypertriglyceridemia. Recent Findings More than 300 genetic loci have been identified for association with triglyceride levels in large genome-wide association studies. Studies combining the loci into polygenic scores have demonstrated that some hypertriglyceridemia phenotypes previously attributed to monogenic inheritance have a polygenic basis. The new genetic discoveries have opened avenues for the development of more effective triglyceride-lowering treatments and raised interest towards genetic screening and tailored treatments against hypertriglyceridemia. Summary The discovery of multiple genetic loci associated with elevated triglyceride levels has led to improved understanding of the genetic basis of hypertriglyceridemia and opened new translational opportunities.

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Genomic Analysis, Progress and Future Perspectives in Dairy Cattle Selection: A Review

Animals ◽

10.3390/ani11030599 ◽

2021 ◽

Vol 11 (3) ◽

pp. 599

Author(s):

Miguel A. Gutierrez-Reinoso ◽

Pedro M. Aponte ◽

Manuel Garcia-Herreros

Keyword(s):

Dairy Cattle ◽

Production Efficiency ◽

Association Studies ◽

Phenotypic Traits ◽

Progeny Testing ◽

Genome Wide Association Studies ◽

Genetic Progress ◽

Breeding Programs ◽

Increased Risk ◽

Selection Of

Genomics comprises a set of current and valuable technologies implemented as selection tools in dairy cattle commercial breeding programs. The intensive progeny testing for production and reproductive traits based on genomic breeding values (GEBVs) has been crucial to increasing dairy cattle productivity. The knowledge of key genes and haplotypes, including their regulation mechanisms, as markers for productivity traits, may improve the strategies on the present and future for dairy cattle selection. Genome-wide association studies (GWAS) such as quantitative trait loci (QTL), single nucleotide polymorphisms (SNPs), or single-step genomic best linear unbiased prediction (ssGBLUP) methods have already been included in global dairy programs for the estimation of marker-assisted selection-derived effects. The increase in genetic progress based on genomic predicting accuracy has also contributed to the understanding of genetic effects in dairy cattle offspring. However, the crossing within inbred-lines critically increased homozygosis with accumulated negative effects of inbreeding like a decline in reproductive performance. Thus, inaccurate-biased estimations based on empirical-conventional models of dairy production systems face an increased risk of providing suboptimal results derived from errors in the selection of candidates of high genetic merit-based just on low-heritability phenotypic traits. This extends the generation intervals and increases costs due to the significant reduction of genetic gains. The remarkable progress of genomic prediction increases the accurate selection of superior candidates. The scope of the present review is to summarize and discuss the advances and challenges of genomic tools for dairy cattle selection for optimizing breeding programs and controlling negative inbreeding depression effects on productivity and consequently, achieving economic-effective advances in food production efficiency. Particular attention is given to the potential genomic selection-derived results to facilitate precision management on modern dairy farms, including an overview of novel genome editing methodologies as perspectives toward the future.

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Microglia and its genetics in Alzheimer's Disease

Current Alzheimer Research ◽

10.2174/1567205018666211105140732 ◽

2021 ◽

Vol 18 ◽

Author(s):

Xinyan Liang ◽

Haijian Wu ◽

Mark Colt ◽

Xinying Guo ◽

Brock Pluimer ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Immune Cell ◽

Morphological Changes ◽

Association Studies ◽

Unmet Need ◽

Genome Wide Association Studies ◽

Protective Effects ◽

Risk Genes ◽

Main Component

: Alzheimer’s Disease (AD) is the most prevalent form of dementia across the world. While its discovery and pathological manifestations are centered on protein aggregations of amyloid-beta (Aβ) and hyperphosphorylated tau protein, neuroinflammation has emerged in the last decade as a main component of the disease in both pathogenesis and progression. As the main innate immune cell type in central nervous system (CNS), microglia play a very important role in regulating neuroinflammation, which occurs commonly in neurodegenerative conditions including AD. Under inflammatory response, microglia undergo morphological changes and status transition from homeostatic to activated forms. Different microglia subtypes displaying distinct genetic profiles have been identified in AD, and these signatures often link to AD risk genes identified from the genome-wide association studies (GWAS), such as APOE and TREM2. Furthermore, many of AD risk genes are highly enriched in microglia and specifically influence the functions of microglia in pathogenesis, e.g. releasing inflammatory cytokines and clearing Aβ. Therefore, building up a landscape of these risk genes in microglia, based on current preclinical studies and in the context of their pathogenic or protective effects, would largely help us to understand the complexed etiology of AD and provide new insight for the unmet need of effective treatment.

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Abstract 288: Novel Mechanisms of Non-coding Genomic Regulation Identified in Cardiac Disease-in-a-dish Models

Circulation Research ◽

10.1161/res.119.suppl_1.288 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Aditya Kumar ◽

Stephanie Thomas ◽

Kirsten Wong ◽

Kevin Tenerelli ◽

Valentina Lo Sardo ◽

...

Keyword(s):

Heart Attack ◽

Connexin 43 ◽

Disease Risk ◽

Association Studies ◽

Correlation Coefficients ◽

Induced Pluripotent Stem Cell ◽

Genome Wide Association Studies ◽

Isogenic Line ◽

Nucleotide Polymorphisms ◽

Increased Risk

Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) at gene loci that affect cardiovascular function, and while mechanisms in protein-coding loci are obvious, those in non-coding loci are difficult to determine. 9p21 is a recently identified locus associated with increased risk of coronary artery disease (CAD) and myocardial infarction. Associations have implicated SNPs in altering smooth muscle and endothelial cell properties but have not identified adverse effects in cardiomyocytes (CMs) despite enhanced disease risk. Using induced pluripotent stem cell-derived CMs from patients that are homozygous risk/risk (R/R) and non-risk/non-risk (N/N) for 9p21 SNPs and either CAD positive or negative, we assessed CM function when cultured on hydrogels capable of mimicking the fibrotic stiffening associated with disease post-heart attack, i.e. “heart attack-in-a-dish” stiffening from 11 kiloPascals (kPa) to 50 kPa. While all CMs independent of genotype and disease beat synchronously on soft matrices, R/R CMs cultured on dynamically stiffened hydrogels exhibited asynchronous contractions and had significantly lower correlation coefficients versus N/N CMs in the same conditions. Dynamic stiffening reduced connexin 43 expression and gap junction assembly in R/R CMs but not N/N CMs. To eliminate patient-to-patient variability, we created an isogenic line by deleting the 9p21 gene locus from a R/R patient using TALEN-mediated gene editing, i.e. R/R KO. Deletion of the 9p21 locus restored synchronous contractility and organized connexin 43 junctions. As a non-coding locus, 9p21 appears to repress connexin transcription, leading to the phenotypes we observe, but only when the niche is stiffened as in disease. These data are the first to demonstrate that disease-specific niche remodeling, e.g. a “heart attack-in-a-dish” model, can differentially affect CM function depending on SNPs within a non-coding locus.

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Involvement of astrocyte and oligodendrocyte gene sets in migraine

Cephalalgia ◽

10.1177/0333102415618614 ◽

2015 ◽

Vol 36 (7) ◽

pp. 640-647 ◽

Cited By ~ 8

Author(s):

Else Eising ◽

Christiaan de Leeuw ◽

Josine L Min ◽

Verneri Anttila ◽

Mark HG Verheijen ◽

...

Keyword(s):

Migraine With Aura ◽

Genetic Background ◽

Migraine Without Aura ◽

Protein Modification ◽

Association Studies ◽

Cell Types ◽

Familial Hemiplegic Migraine ◽

Genome Wide Association Studies ◽

Brain Disorder ◽

Gene Sets

Background Migraine is a common episodic brain disorder characterized by recurrent attacks of severe unilateral headache and additional neurological symptoms. Two main migraine types can be distinguished based on the presence of aura symptoms that can accompany the headache: migraine with aura and migraine without aura. Multiple genetic and environmental factors confer disease susceptibility. Recent genome-wide association studies (GWAS) indicate that migraine susceptibility genes are involved in various pathways, including neurotransmission, which have already been implicated in genetic studies of monogenic familial hemiplegic migraine, a subtype of migraine with aura. Methods To further explore the genetic background of migraine, we performed a gene set analysis of migraine GWAS data of 4954 clinic-based patients with migraine, as well as 13,390 controls. Curated sets of synaptic genes and sets of genes predominantly expressed in three glial cell types (astrocytes, microglia and oligodendrocytes) were investigated. Discussion Our results show that gene sets containing astrocyte- and oligodendrocyte-related genes are associated with migraine, which is especially true for gene sets involved in protein modification and signal transduction. Observed differences between migraine with aura and migraine without aura indicate that both migraine types, at least in part, seem to have a different genetic background.

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Genetic Variability in Molecular Pathways Implicated in Alzheimer's Disease: A Comprehensive Review

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.646901 ◽

2021 ◽

Vol 13 ◽

Author(s):

David Vogrinc ◽

Katja Goričar ◽

Vita Dolžan

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Age Of Onset ◽

Association Studies ◽

The Elderly ◽

Gene Clustering ◽

Molecular Pathways ◽

Genome Wide Association Studies ◽

Cellular Processes ◽

Increased Risk

Alzheimer's disease (AD) is a complex neurodegenerative disease, affecting a significant part of the population. The majority of AD cases occur in the elderly with a typical age of onset of the disease above 65 years. AD presents a major burden for the healthcare system and since population is rapidly aging, the burden of the disease will increase in the future. However, no effective drug treatment for a full-blown disease has been developed to date. The genetic background of AD is extensively studied; numerous genome-wide association studies (GWAS) identified significant genes associated with increased risk of AD development. This review summarizes more than 100 risk loci. Many of them may serve as biomarkers of AD progression, even in the preclinical stage of the disease. Furthermore, we used GWAS data to identify key pathways of AD pathogenesis: cellular processes, metabolic processes, biological regulation, localization, transport, regulation of cellular processes, and neurological system processes. Gene clustering into molecular pathways can provide background for identification of novel molecular targets and may support the development of tailored and personalized treatment of AD.

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A Network-based Deep Learning Framework Catalyzes GWAS and Multi-Omics Findings to Biology and Drug Repurposing for Alzheimer's Disease

10.1101/2021.10.20.465087 ◽

2021 ◽

Author(s):

Jielin Xu ◽

Yuan Hou ◽

Yadi Zhou ◽

Ming Hu ◽

Feixiong Cheng

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Deep Learning ◽

Disease Risk ◽

Association Studies ◽

Open Chromatin ◽

Genome Wide Association Studies ◽

Risk Genes ◽

Learning Framework ◽

Protein Interactome

Human genome sequencing studies have identified numerous loci associated with complex diseases, including Alzheimer's disease (AD). Translating human genetic findings (i.e., genome-wide association studies [GWAS]) to pathobiology and therapeutic discovery, however, remains a major challenge. To address this critical problem, we present a network topology-based deep learning framework to identify disease-associated genes (NETTAG). NETTAG is capable of integrating multi-genomics data along with the protein-protein interactome to infer putative risk genes and drug targets impacted by GWAS loci. Specifically, we leverage non-coding GWAS loci effects on expression quantitative trait loci (eQTLs), histone-QTLs, and transcription factor binding-QTLs, enhancers and CpG islands, promoter regions, open chromatin, and promoter flanking regions. The key premises of NETTAG are that the disease risk genes exhibit distinct functional characteristics compared to non-risk genes and therefore can be distinguished by their aggregated genomic features under the human protein interactome. Applying NETTAG to the latest AD GWAS data, we identified 156 putative AD-risk genes (i.e., APOE, BIN1, GSK3B, MARK4, and PICALM). We showed that predicted risk genes are: 1) significantly enriched in AD-related pathobiological pathways, 2) more likely to be differentially expressed regarding transcriptome and proteome of AD brains, and 3) enriched in druggable targets with approved medicines (i.e., choline and ibudilast). In summary, our findings suggest that understanding of human pathobiology and therapeutic development could benefit from a network-based deep learning methodology that utilizes GWAS findings under the multimodal genomic analyses.

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