scholarly journals Sex-specific regulation of weight and puberty by the Lin28/let-7 axis

2015 ◽  
Vol 228 (3) ◽  
pp. 179-191 ◽  
Author(s):  
Christina Corre ◽  
Gen Shinoda ◽  
Hao Zhu ◽  
Diana L Cousminer ◽  
Christine Crossman ◽  
...  
Keyword(s):  
Late Onset ◽  
Pubertal Timing ◽  
Association Studies ◽  
Growth Patterns ◽  
Age At Menarche ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Male And Female ◽  
Female Mice ◽  
Specific Manner

Growth and pubertal timing differ in boys and girls. Variants in/nearLIN28Bassociate with age at menarche (AAM) in genome-wide association studies and some AAM-related variants associate with growth in a sex-specific manner. Sex-specific growth patterns in response toLin28bperturbation have been detected in mice, and overexpression ofLin28ahas been shown to alter pubertal timing in female mice. To investigate further howLin28aandLin28baffect growth and puberty in both males and females, we evaluatedLin28bloss-of-function (LOF) mice andLin28again-of-function (GOF) mice. Because bothLin28aandLin28bcan act via the conserved microRNAlet-7, we also examinedlet-7GOF mice. As reported previously,Lin28bLOF led to lighter body weights only in male mice whileLin28aGOF yielded heavier mice of both sexes.Let-7GOF mice weighed less than controls, and males were more affected than females. Timing of puberty was assessed by vaginal opening (VO) and preputial separation (PS). MaleLin28bLOF and malelet-7GOF, but not female, mice displayed alteration of pubertal timing, with later PS than controls. In contrast, both male and femaleLin28aGOF mice displayed late onset of puberty. Together, these data point toward a complex system of regulation byLin28a,Lin28b, andlet-7, in whichLin28bandlet-7can impact both puberty and growth in a sex-specific manner, raising the possibility that this pathway may contribute to differential regulation of male and female growth and puberty in humans.

scholarly journals Gene4PD: A Comprehensive Genetic Database of Parkinson’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Bin Li ◽  
Guihu Zhao ◽  
Qiao Zhou ◽  
Yali Xie ◽  
Zheng Wang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Association Studies ◽  
Age At Onset ◽  
Genetic Data ◽  
Genome Wide Association Studies ◽  
Onset Age ◽  
Loss Of Function

Parkinson’s disease (PD) is a complex neurodegenerative disorder with a strong genetic component. A growing number of variants and genes have been reported to be associated with PD; however, there is no database that integrate different type of genetic data, and support analyzing of PD-associated genes (PAGs). By systematic review and curation of multiple lines of public studies, we integrate multiple layers of genetic data (rare variants and copy-number variants identified from patients with PD, associated variants identified from genome-wide association studies, differentially expressed genes, and differential DNA methylation genes) and age at onset in PD. We integrated five layers of genetic data (8302 terms) with different levels of evidences from more than 3,000 studies and prioritized 124 PAGs with strong or suggestive evidences. These PAGs were identified to be significantly interacted with each other and formed an interconnected functional network enriched in several functional pathways involved in PD, suggesting these genes may contribute to the pathogenesis of PD. Furthermore, we identified 10 genes were associated with a juvenile-onset (age ≤ 30 years), 11 genes were associated with an early-onset (age of 30–50 years), whereas another 10 genes were associated with a late-onset (age > 50 years). Notably, the AAOs of patients with loss of function variants in five genes were significantly lower than that of patients with deleterious missense variants, while patients with VPS13C (P = 0.01) was opposite. Finally, we developed an online database named Gene4PD (http://genemed.tech/gene4pd) which integrated published genetic data in PD, the PAGs, and 63 popular genomic data sources, as well as an online pipeline for prioritize risk variants in PD. In conclusion, Gene4PD provides researchers and clinicians comprehensive genetic knowledge and analytic platform for PD, and would also improve the understanding of pathogenesis in PD.

scholarly journals ZCWPW1 loss-of-function variants in Alzheimer's Disease

2021 ◽  
Author(s):  
Fahri Küçükali ◽  
Katrin Nußbaumer ◽  
Jasper Van Dongen ◽  
Elisabeth Hens ◽  
Céline Bellenguez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Potential Risk ◽  
Rare Variants ◽  
Late Onset ◽  
Association Studies ◽  
Risk Haplotype ◽  
Genome Wide Association Studies ◽  
Sequencing Analysis ◽  
Loss Of Function

Genome-wide association studies (GWAS) have identified more than 75 genetic risk loci for Alzheimer's Disease (AD), however for a substantial portion of these loci the genetic variants or genes directly involved in AD risk remain to be found. A GWAS locus defined by the index SNP rs1476679 in ZCWPW1 is one of the largest AD loci as the association signal spans 56 potential risk genes. The three most compelling candidate genes in this locus are ZCWPW1, PILRA and PILRB, based on genetic, transcriptomic, and proteomic evidence. We performed amplicon-based target enrichment and next-generation sequencing of the exons, exon-intron boundaries, and UTRs of ZCWPW1, PILRA and PILRB on an Illumina MiSeq platform in 1048 Flanders-Belgian late-onset AD patients and 1037 matched healthy controls. Along with the single-marker association testing, the combined effect of Sanger-validated rare variants was evaluated in SKAT-O. No common variants (n = 40) were associated with AD. We identified 20 validated deleterious rare variants (MAF < 1%, CADD score ≥ 20), 14 of which in ZCWPW1. This included 4 predicted loss-of-function (LoF) mutations that were exclusively found in patients (P = 0.011). Haplotype sharing analysis revealed distant common ancestors for two LoF mutations. Single-molecule long-read Nanopore sequencing analysis unveiled that all LoF mutations are phased with the risk haplotype in the locus. Our results support the recent report for the role of ultra-rare LoF ZCWPW1 variants in AD and suggest a potential risk mechanism for AD through ZCWPW1 haploinsufficiency.

scholarly journals Gene4PD: a comprehensive genetic database of Parkinson's disease

2020 ◽  
Author(s):  
Bin Li ◽  
Guihu Zhao ◽  
Qiao Zhou ◽  
Yali Xie ◽  
Zheng Wang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Permutation Test ◽  
Association Studies ◽  
Genetic Data ◽  
Genome Wide Association Studies ◽  
Onset Age ◽  
Loss Of Function

Abstract BackgroundParkinson's disease (PD) is a complex neurodegenerative disorder with a strong genetic component. A growing number of variants and genes have been reported to be associated with PD; however, there is no database that integrate different type of genetic data, and support analyzing of PD-associated genes (PAGs).MethodsBy systematic review and curation of multiple lines of public studies, we integrate multiple layers of genetic data (rare variants and copy-number variants identified from patients with PD, associated variants identified from genome-wide association studies, differential expression genes, and differential DNA methylation genes) and clinical data in PD. A weighted scoring system was employed to prioritize PAGs. Permutation test and protein-protein interaction network was used to evaluate the interconnectivity and functional correlation among the PAGs. The relationship between AAO and PAGs was further analyzed. A PHP-based web framework was used to construct a database. ResultWe integrated five layers of genetic data with different levels of evidences from more than 3,000 studies and prioritized 124 PAGs with strong or suggestive evidences. These PAGs were identified to be significantly interacted with each other and formed an interconnected functional network enriched in several functional pathways involved in PD, suggesting these genes may contribute to the pathogenesis of PD, which also highlighting the reliability of these genetic data for PD. Furthermore, we identified 10 genes were associated with a juvenile-onset (age ≤ 30 years), 11 genes were associated with an early-onset (age of 30–50 years), whereas another 10 genes were associated with a late-onset (age > 50 years). Notably, the AAOs of patients with loss of function variants in five genes (GCH1, PINK1, PRKN, FBXO7, ATP13A2) were significantly lower than that of patients with deleterious missense variants, while patients with VPS13C (P = 0.01) was opposite. Finally, we developed an online database named Gene4PD (http://genemed.tech/gene4pd) which integrated published genetic data in PD, the PAGs, and 63 popular genomic data sources, as well as an online pipeline for prioritize risk variants in PD.ConclusionGene4PD provides researchers and clinicians comprehensive genetic knowledge and analytic platform for PD, and would also improve the understanding of pathogenesis in PD.Availability and Implementation: Gene4PD can be freely accessed at http://genemed.tech/gene4pd.

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

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.

scholarly journals Genetic architecture of schizophrenia: a review of major advancements

2021 ◽  
pp. 1-10
Author(s):  
Sophie E. Legge ◽  
Marcos L. Santoro ◽  
Sathish Periyasamy ◽  
Adeniran Okewole ◽  
Arsalan Arsalan ◽  
...  
Keyword(s):  
Genetic Architecture ◽  
Association Studies ◽  
Copy Number Variants ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Genetic Loci ◽  
Significant Enrichment ◽  
High Heritability ◽  
Coding Variants

Abstract Schizophrenia is a severe psychiatric disorder with high heritability. Consortia efforts and technological advancements have led to a substantial increase in knowledge of the genetic architecture of schizophrenia over the past decade. In this article, we provide an overview of the current understanding of the genetics of schizophrenia, outline remaining challenges, and summarise future directions of research. World-wide collaborations have resulted in genome-wide association studies (GWAS) in over 56 000 schizophrenia cases and 78 000 controls, which identified 176 distinct genetic loci. The latest GWAS from the Psychiatric Genetics Consortium, available as a pre-print, indicates that 270 distinct common genetic loci have now been associated with schizophrenia. Polygenic risk scores can currently explain around 7.7% of the variance in schizophrenia case-control status. Rare variant studies have implicated eight rare copy-number variants, and an increased burden of loss-of-function variants in SETD1A, as increasing the risk of schizophrenia. The latest exome sequencing study, available as a pre-print, implicates a burden of rare coding variants in a further nine genes. Gene-set analyses have demonstrated significant enrichment of both common and rare genetic variants associated with schizophrenia in synaptic pathways. To address current challenges, future genetic studies of schizophrenia need increased sample sizes from more diverse populations. Continued expansion of international collaboration will likely identify new genetic regions, improve fine-mapping to identify causal variants, and increase our understanding of the biology and mechanisms of schizophrenia.

scholarly journals Cis-Segregation of c.1171C>T Stop Codon (p.R391*) in SERPINC1 Gene and c.1691G>A Transition (p.R506Q) in F5 Gene and Selected GWAS Multilocus Approach in Inherited Thrombophilia

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 934
Author(s):  
Donato Gemmati ◽  
Giovanna Longo ◽  
Eugenia Franchini ◽  
Juliana Araujo Silva ◽  
Ines Gallo ◽  
...  
Keyword(s):  
At Risk ◽  
Stop Codon ◽  
Association Studies ◽  
Premature Stop Codon ◽  
Large Family ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Gene Markers ◽  
Inherited Thrombophilia ◽  
Fv Leiden

Inherited thrombophilia (e.g., venous thromboembolism, VTE) is due to rare loss-of-function mutations in anticoagulant factors genes (i.e., SERPINC1, PROC, PROS1), common gain-of-function mutations in procoagulant factors genes (i.e., F5, F2), and acquired risk conditions. Genome Wide Association Studies (GWAS) recently recognized several genes associated with VTE though gene defects may unpredictably remain asymptomatic, so calculating the individual genetic predisposition is a challenging task. We investigated a large family with severe, recurrent, early-onset VTE in which two sisters experienced VTE during pregnancies characterized by a perinatal in-utero thrombosis in the newborn and a life-saving pregnancy-interruption because of massive VTE, respectively. A nonsense mutation (CGA > TGA) generating a premature stop-codon (c.1171C>T; p.R391*) in the exon 6 of SERPINC1 gene (1q25.1) causing Antithrombin (AT) deficiency and the common missense mutation (c.1691G>A; p.R506Q) in the exon 10 of F5 gene (1q24.2) (i.e., FV Leiden; rs6025) were coinherited in all the symptomatic members investigated suspecting a cis-segregation further confirmed by STR-linkage-analyses [i.e., SERPINC1 IVS5 (ATT)5–18, F5 IVS2 (AT)6–33 and F5 IVS11 (GT)12–16] and SERPINC1 intragenic variants (i.e., rs5878 and rs677). A multilocus investigation of blood-coagulation balance genes detected the coexistence of FV Leiden (rs6025) in trans with FV HR2-haplotype (p.H1299R; rs1800595) in the aborted fetus, and F11 rs2289252, F12 rs1801020, F13A1 rs5985, and KNG1 rs710446 in the newborn and other members. Common selected gene variants may strongly synergize with less common mutations tuning potential life-threatening conditions when combined with rare severest mutations. Merging classic and newly GWAS-identified gene markers in at risk families is mandatory for VTE risk estimation in the clinical practice, avoiding partial risk score evaluation in unrecognized at risk patients.

scholarly journals The clinical utility of gene testing for Alzheimer’s disease

2011 ◽  
Vol 3 (1) ◽  
pp. 1 ◽  
Author(s):  
Emily R. Atkins ◽  
Peter K. Panegyres
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Onset ◽  
Late Onset ◽  
Association Studies ◽  
Susceptibility Gene ◽  
Genome Wide Association Studies ◽  
Apoe Ε4 ◽  
Gene Testing ◽  
A Genome

Alzheimer’s disease (AD) is the largest cause of dementia, affecting 35.6 million people in 2010. Amyloid precursor protein, presenilin 1 and presenilin 2 mutations are known to cause familial early-onset AD, whereas apolipoprotein E (APOE) ε4 is a susceptibility gene for late-onset AD. The genes for phosphatidylinositol- binding clathrin assembly protein, clusterin and complement receptor 1 have recently been described by genome-wide association studies as potential risk factors for lateonset AD. Also, a genome association study using single neucleotide polymorphisms has identified an association of neuronal sortilin related receptor and late-onset AD. Gene testing, and also predictive gene testing, may be of benefit in suspected familial early-onset AD however it adds little to the diagnosis of lateonset AD and does not alter the treatment. We do not recommend APOE ε4 genotyping.

scholarly journals Partitioning heritability by functional category using GWAS summary statistics

2015 ◽  
Author(s):  
Hilary Kiyo Finucane ◽  
Brendan Bulik-Sullivan ◽  
Alexander Gusev ◽  
Gosia Trynka ◽  
Yakir Reshef ◽  
...  
Keyword(s):  
Association Studies ◽  
Smoking Behavior ◽  
Complex Diseases ◽  
New Method ◽  
Age At Menarche ◽  
Genome Wide Association Studies ◽  
Summary Statistics ◽  
Cell Type ◽  
Genome Wide ◽  
Cell Type Specific

Recent work has demonstrated that some functional categories of the genome contribute disproportionately to the heritability of complex diseases. Here, we analyze a broad set of functional elements, including cell-type-specific elements, to estimate their polygenic contributions to heritability in genome-wide association studies (GWAS) of 17 complex diseases and traits spanning a total of 1.3 million phenotype measurements. To enable this analysis, we introduce a new method for partitioning heritability from GWAS summary statistics while controlling for linked markers. This new method is computationally tractable at very large sample sizes, and leverages genome-wide information. Our results include a large enrichment of heritability in conserved regions across many traits; a very large immunological disease-specific enrichment of heritability in FANTOM5 enhancers; and many cell-type-specific enrichments including significant enrichment of central nervous system cell types in body mass index, age at menarche, educational attainment, and smoking behavior. These results demonstrate that GWAS can aid in understanding the biological basis of disease and provide direction for functional follow-up.

scholarly journals Age-related late-onset disease heritability patterns and implications for genome-wide association studies

2018 ◽  
Author(s):  
Roman Teo Oliynyk
Keyword(s):  
Old Age ◽  
Cumulative Incidence ◽  
Late Onset ◽  
Association Studies ◽  
Genome Wide Association ◽  
Risk Scores ◽  
Cerebral Stroke ◽  
Genome Wide Association Studies ◽  
Polygenic Risk ◽  
Genome Wide

AbstractBackgroundGenome-wide association studies and other computational biology techniques are gradually discovering the causal gene variants that contribute to late-onset human diseases. After more than a decade of genome-wide association study efforts, these can account for only a fraction of the heritability implied by familial studies, the so-called “missing heritability” problem.MethodsComputer simulations of polygenic late-onset diseases in an aging population have quantified the risk allele frequency decrease at older ages caused by individuals with higher polygenic risk scores becoming ill proportionately earlier. This effect is most prominent for diseases characterized by high cumulative incidence and high heritability, examples of which include Alzheimer’s disease, coronary artery disease, cerebral stroke, and type 2 diabetes.ResultsThe incidence rate for late-onset diseases grows exponentially for decades after early onset ages, guaranteeing that the cohorts used for genome-wide association studies overrepresent older individuals with lower polygenic risk scores, whose disease cases are disproportionately due to environmental causes such as old age itself. This mechanism explains the decline in clinical predictive power with age and the lower discovery power of familial studies of heritability and genome-wide association studies. It also explains the relatively constant-with-age heritability found for late-onset diseases of lower prevalence, exemplified by cancers.ConclusionsFor late-onset polygenic diseases showing high cumulative incidence together with high initial heritability, rather than using relatively old age-matched cohorts, study cohorts combining the youngest possible cases with the oldest possible controls may significantly improve the discovery power of genome-wide association studies.

scholarly journals Strain screen and haplotype association mapping of wheel running in inbred mouse strains

2010 ◽  
Vol 109 (3) ◽  
pp. 623-634 ◽  
Author(s):  
J. Timothy Lightfoot ◽  
Larry Leamy ◽  
Daniel Pomp ◽  
Michael J. Turner ◽  
Anthony A. Fodor ◽  
...  
Keyword(s):  
Physical Activity ◽  
Association Mapping ◽  
Wheel Running ◽  
Association Studies ◽  
Mouse Strains ◽  
Haplotype Association ◽  
Male And Female ◽  
Female Mice ◽  
Running Activity ◽  
Wheel Running Activity

Previous genetic association studies of physical activity, in both animal and human models, have been limited in number of subjects and genetically homozygous strains used as well as number of genomic markers available for analysis. Expansion of the available mouse physical activity strain screens and the recently published dense single-nucleotide polymorphism (SNP) map of the mouse genome (≈8.3 million SNPs) and associated statistical methods allowed us to construct a more generalizable map of the quantitative trait loci (QTL) associated with physical activity. Specifically, we measured wheel running activity in male and female mice (average age 9 wk) in 41 inbred strains and used activity data from 38 of these strains in a haplotype association mapping analysis to determine QTL associated with activity. As seen previously, there was a large range of activity patterns among the strains, with the highest and lowest strains differing significantly in daily distance run (27.4-fold), duration of activity (23.6-fold), and speed (2.9-fold). On a daily basis, female mice ran further (24%), longer (13%), and faster (11%). Twelve QTL were identified, with three (on Chr. 12, 18, and 19) in both male and female mice, five specific to males, and four specific to females. Eight of the 12 QTL, including the 3 general QTL found for both sexes, fell into intergenic areas. The results of this study further support the findings of a moderate to high heritability of physical activity and add general genomic areas applicable to a large number of mouse strains that can be further mined for candidate genes associated with regulation of physical activity. Additionally, results suggest that potential genetic mechanisms arising from traditional noncoding regions of the genome may be involved in regulation of physical activity.

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