SMARCA2 common variant association and rare variant excess in Schizophrenia patients from an Algerian Trio Cohort

2011 ◽  
Vol 26 (S2) ◽  
pp. 1346-1346
Author(s):  
D. Benmessaoud ◽  
A.-M. Lepagnol-Bestel ◽  
M. Delepine ◽  
J. Hager ◽  
J.-M. Moalic ◽  
...  
Keyword(s):  
Rare Variants ◽  
Association Studies ◽  
Common Variant ◽  
Genome Wide Association Studies ◽  
Common Variants ◽  
Fisher Test ◽  
Coding Regions ◽  
Genome Wide ◽  
Whole Exome ◽  
Positive Evolution

Genome wide association studies (GWAS) of Schizophrenia (SZ) patients have identified common variants in ten genes including SMARCA2 (Koga et al., HMG, 2009). We found that the SZ-GWAS genes are part of an interacting network centered on SMARCA2 (Loe-Mie et al., HMG, 2010). Furthermore, SMARCA2 was found disrupted in SZ (Walsh et al., Science, 2008). SMARCA2 encodes the ATPase (BRM) of the SWI/SNF chromatin remodeling complex that is at the interface of genome and environmental adaptation.Taking advantage of an Algerian trio cohort of one hundred SZ patients (Benmessaoud et al., BMC Psychiatry, 2008), we replicated the association of SNP rs2296212 localized in exon 33, already shown associated in Koga study and resulting in D1546E amino acid change in the SMARCA2 protein. We studied SMARCA2 codons and found that exon 33 displays a signature of positive evolution in the primate lineage.Our working hypothesis is that the coding regions displaying positive selection are target of novel rare variants. To address this question, we sequenced two exons displaying positive evolution and one exon without evidence of positive evolution.We found (i) that rare variants are significantly in excess in SZ-patients compared to their parents (p = 0.038, Fisher test) and (ii) a higher proportion of rare variants in the primate-accelerated exons compared with the non-evolutionary exon in SZ-patients (p = 0.032, Fisher test).SMARCA2 exon sequencing and whole exome sequencing from patients harboring SNP rs2296212 common variant are under progress. Altogether, these results are expected to give new insights into the genetic architecture of SZ.

scholarly journals Deep genotype imputation captures virtually all heritability of autoimmune vitiligo

2020 ◽  
Vol 29 (5) ◽  
pp. 859-863 ◽  
Author(s):  
Genevieve H L Roberts ◽  
Stephanie A Santorico ◽  
Richard A Spritz
Keyword(s):  
Complex Disease ◽  
Rare Variants ◽  
Association Studies ◽  
Genotype Imputation ◽  
Genome Wide Association Studies ◽  
Common Variants ◽  
Genome Wide ◽  
Autoimmune Vitiligo ◽  
Family Based ◽  
Project Data

Abstract Autoimmune vitiligo is a complex disease involving polygenic risk from at least 50 loci previously identified by genome-wide association studies. The objectives of this study were to estimate and compare vitiligo heritability in European-derived patients using both family-based and ‘deep imputation’ genotype-based approaches. We estimated family-based heritability (h2FAM) by vitiligo recurrence among a total 8034 first-degree relatives (3776 siblings, 4258 parents or offspring) of 2122 unrelated vitiligo probands. We estimated genotype-based heritability (h2SNP) by deep imputation to Haplotype Reference Consortium and the 1000 Genomes Project data in unrelated 2812 vitiligo cases and 37 079 controls genotyped genome wide, achieving high-quality imputation from markers with minor allele frequency (MAF) as low as 0.0001. Heritability estimated by both approaches was exceedingly high; h2FAM = 0.75–0.83 and h2SNP = 0.78. These estimates are statistically identical, indicating there is essentially no remaining ‘missing heritability’ for vitiligo. Overall, ~70% of h2SNP is represented by common variants (MAF > 0.01) and 30% by rare variants. These results demonstrate that essentially all vitiligo heritable risk is captured by array-based genotyping and deep imputation. These findings suggest that vitiligo may provide a particularly tractable model for investigation of complex disease genetic architecture and predictive aspects of personalized medicine.

scholarly journals Contributions of Function-Altering Variants in Genes Implicated in Pubertal Timing and Body Mass for Self-Limited Delayed Puberty

2017 ◽  
Vol 103 (2) ◽  
pp. 649-659 ◽  
Author(s):  
Sasha R Howard ◽  
Leonardo Guasti ◽  
Ariel Poliandri ◽  
Alessia David ◽  
Claudia P Cabrera ◽  
...  
Keyword(s):  
Body Mass ◽  
Rare Variants ◽  
Association Studies ◽  
Delayed Puberty ◽  
Age At Menarche ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Whole Exome ◽  
Timing Of Puberty

Abstract Context Self-limited delayed puberty (DP) is often associated with a delay in physical maturation, but although highly heritable the causal genetic factors remain elusive. Genome-wide association studies of the timing of puberty have identified multiple loci for age at menarche in females and voice break in males, particularly in pathways controlling energy balance. Objective/Main Outcome Measures We sought to assess the contribution of rare variants in such genes to the phenotype of familial DP. Design/Patients We performed whole-exome sequencing in 67 pedigrees (125 individuals with DP and 35 unaffected controls) from our unique cohort of familial self-limited DP. Using a whole-exome sequencing filtering pipeline one candidate gene [fat mass and obesity–associated gene (FTO)] was identified. In silico, in vitro, and mouse model studies were performed to investigate the pathogenicity of FTO variants and timing of puberty in FTO+/− mice. Results We identified potentially pathogenic, rare variants in genes in linkage disequilibrium with genome-wide association studies of age at menarche loci in 283 genes. Of these, five genes were implicated in the control of body mass. After filtering for segregation with trait, one candidate, FTO, was retained. Two FTO variants, found in 14 affected individuals from three families, were also associated with leanness in these patients with DP. One variant (p.Leu44Val) demonstrated altered demethylation activity of the mutant protein in vitro. Fto+/− mice displayed a significantly delayed timing of pubertal onset (P < 0.05). Conclusions Mutations in genes implicated in body mass and timing of puberty in the general population may contribute to the pathogenesis of self-limited DP.

scholarly journals Detecting association of rare and common variants by adaptive combination of P-values

2015 ◽  
Vol 97 ◽  
Author(s):  
YAJING ZHOU ◽  
YONG WANG
Keyword(s):  
Rare Variants ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Common Variants ◽  
Next Generation Sequencing Technology ◽  
Adaptive Combination ◽  
Genome Wide ◽  
Wide Range ◽  
Causal Variants ◽  
Burden Tests

SummaryGenome-wide association studies (GWAS) can detect common variants associated with diseases. Next generation sequencing technology has made it possible to detect rare variants. Most of association tests, including burden tests and nonburden tests, mainly target rare variants by upweighting rare variant effects and downweighting common variant effects. But there is increasing evidence that complex diseases are caused by both common and rare variants. In this paper, we extend the ADA method (adaptive combination of P-values; Lin et al., 2014) for rare variants only and propose a RC-ADA method (common and rare variants by adaptive combination of P-values). Our proposed method combines the per-site P-values with the weights based on minor allele frequencies (MAFs). The RC-ADA is robust to directions of effects of causal variants and inclusion of a high proportion of neutral variants. The performance of the RC-ADA method is compared with several other association methods. Extensive simulation studies show that the RC-ADA method is more powerful than other association methods over a wide range of models.

scholarly journals Unique roles of rare variants in the genetics of complex diseases in humans

2020 ◽  
Vol 66 (1) ◽  
pp. 11-23
Author(s):  
Yukihide Momozawa ◽  
Keijiro Mizukami
Keyword(s):  
Rare Variants ◽  
Disease Risk ◽  
Association Studies ◽  
Complex Diseases ◽  
Genome Wide Association Studies ◽  
Whole Genome ◽  
Sequencing Analysis ◽  
Common Variants ◽  
Distinctive Features ◽  
Genome Wide

AbstractGenome-wide association studies have identified >10,000 genetic variants associated with various phenotypes and diseases. Although the majority are common variants, rare variants with >0.1% of minor allele frequency have been investigated by imputation and using disease-specific custom SNP arrays. Rare variants sequencing analysis mainly revealed have played unique roles in the genetics of complex diseases in humans due to their distinctive features, in contrast to common variants. Unique roles are hypothesis-free evidence for gene causality, a precise target of functional analysis for understanding disease mechanisms, a new favorable target for drug development, and a genetic marker with high disease risk for personalized medicine. As whole-genome sequencing continues to identify more rare variants, the roles associated with rare variants will also increase. However, a better estimation of the functional impact of rare variants across whole genome is needed to enhance their contribution to improvements in human health.

scholarly journals The open targets post-GWAS analysis pipeline

2020 ◽  
Vol 36 (9) ◽  
pp. 2936-2937 ◽  
Author(s):  
Gareth Peat ◽  
William Jones ◽  
Michael Nuhn ◽  
José Carlos Marugán ◽  
William Newell ◽  
...  
Keyword(s):  
Drug Targets ◽  
Gene Expression Regulation ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Protein Coding ◽  
Data Resource ◽  
Coding Regions ◽  
Genome Wide ◽  
Causal Genes ◽  
Interactive Data

Abstract Motivation Genome-wide association studies (GWAS) are a powerful method to detect even weak associations between variants and phenotypes; however, many of the identified associated variants are in non-coding regions, and presumably influence gene expression regulation. Identifying potential drug targets, i.e. causal protein-coding genes, therefore, requires crossing the genetics results with functional data. Results We present a novel data integration pipeline that analyses GWAS results in the light of experimental epigenetic and cis-regulatory datasets, such as ChIP-Seq, Promoter-Capture Hi-C or eQTL, and presents them in a single report, which can be used for inferring likely causal genes. This pipeline was then fed into an interactive data resource. Availability and implementation The analysis code is available at www.github.com/Ensembl/postgap and the interactive data browser at postgwas.opentargets.io.

scholarly journals Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

Nature ◽  
2021 ◽  
Vol 590 (7845) ◽  
pp. 290-299 ◽  
Author(s):  
Daniel Taliun ◽  
◽  
Daniel N. Harris ◽  
Michael D. Kessler ◽  
Jedidiah Carlson ◽  
...  
Keyword(s):  
Rare Variants ◽  
Sequence Data ◽  
Association Studies ◽  
Genotype Imputation ◽  
Genome Wide Association Studies ◽  
Phenotypic Data ◽  
Treatment And Prevention ◽  
Genome Wide ◽  
Diverse Backgrounds ◽  
Unmapped Reads

AbstractThe Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1. In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.

scholarly journals Impact of Pre and Post Variant Filtration Strategies on Imputation

2020 ◽  
Author(s):  
Celine Charon ◽  
Rodrigue Allodji ◽  
Vincent Meyer ◽  
Jean-François Deleuze
Keyword(s):  
Quality Control ◽  
Rare Variants ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Direct Effects ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Conservative Post

Abstract Quality control methods for genome-wide association studies and fine mapping are commonly used for imputation, however, they result in loss of many single nucleotide polymorphisms (SNPs). To investigate the consequences of filtration on imputation, we studied the direct effects on the number of markers, their allele frequencies, imputation quality scores and post-filtration events. We pre-phrased 1,031 genotyped individuals from diverse ethnicities and compared the imputed variants to 1,089 NCBI recorded individuals for additional validation.Without variant pre-filtration based on quality control (QC), we observed no impairment in the imputation of SNPs that failed QC whereas with pre-filtration there was an overall loss of information. Significant differences between frequencies with and without pre-filtration were found only in the range of very rare (5E-04-1E-03) and rare variants (1E-03-5E-03) (p < 1E-04). Increasing the post-filtration imputation quality score from 0.3 to 0.8 reduced the number of single nucleotide variants (SNVs) <0.001 2.5 fold with or without QC pre-filtration and halved the number of very rare variants (5E-04). As a result, to maintain confidence and enough SNVs, we propose here a 2-step post-filtration approach to increase the number of very rare and rare variants compared to conservative post-filtration methods.

Abstract 367: Extreme High-Density Lipoprotein Cholesterol Genetics: An Assortment of Large and Small Polygenic Effects

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Jacqueline S Dron ◽  
Jian Wang ◽  
Cécile Low-Kam ◽  
Sumeet A Khetarpal ◽  
John F Robinson ◽  
...  
Keyword(s):  
Large Scale ◽  
Genetic Basis ◽  
Rare Variants ◽  
Association Studies ◽  
Density Lipoprotein ◽  
Copy Number Variations ◽  
Genome Wide Association Studies ◽  
Common Variants ◽  
Targeted Next Generation Sequencing ◽  
Common Genetic Variants

Rationale: Although HDL-C levels are known to have a complex genetic basis, most studies have focused solely on identifying rare variants with large phenotypic effects to explain extreme HDL-C phenotypes. Objective: Here we concurrently evaluate the contribution of both rare and common genetic variants, as well as large-scale copy number variations (CNVs), towards extreme HDL-C concentrations. Methods: In clinically ascertained patients with low ( N =136) and high ( N =119) HDL-C profiles, we applied our targeted next-generation sequencing panel (LipidSeq TM ) to sequence genes involved in HDL metabolism, which were subsequently screened for rare variants and CNVs. We also developed a novel polygenic trait score (PTS) to assess patients’ genetic accumulations of common variants that have been shown by genome-wide association studies to associate primarily with HDL-C levels. Two additional cohorts of patients with extremely low and high HDL-C (total N =1,746 and N =1,139, respectively) were used for PTS validation. Results: In the discovery cohort, 32.4% of low HDL-C patients carried rare variants or CNVs in primary ( ABCA1 , APOA1 , LCAT ) and secondary ( LPL , LMF1 , GPD1 , APOE ) HDL-C–altering genes. Additionally, 13.4% of high HDL-C patients carried rare variants or CNVs in primary ( SCARB1 , CETP , LIPC , LIPG ) and secondary ( APOC3 , ANGPTL4 ) HDL-C–altering genes. For polygenic effects, patients with abnormal HDL-C profiles but without rare variants or CNVs were ~2-fold more likely to have an extreme PTS compared to normolipidemic individuals, indicating an increased frequency of common HDL-C–associated variants in these patients. Similar results in the two validation cohorts demonstrate that this novel PTS successfully quantifies common variant accumulation, further characterizing the polygenic basis for extreme HDL-C phenotypes. Conclusions: Patients with extreme HDL-C levels have various combinations of rare variants, common variants, or CNVs driving their phenotypes. Fully characterizing the genetic basis of HDL-C levels must extend to encompass multiple types of genetic determinants—not just rare variants—to further our understanding of this complex, controversial quantitative trait.

scholarly journals Genes identified through genome-wide association studies of osteonecrosis in childhood acute lymphoblastic leukemia patients

2019 ◽  
Vol 20 (17) ◽  
pp. 1189-1197 ◽  
Author(s):  
Vincent Gagné ◽  
Anne Aubry-Morin ◽  
Maria Plesa ◽  
Rachid Abaji ◽  
Kateryna Petrykey ◽  
...  
Keyword(s):  
Association Studies ◽  
Lymphoblastic Leukemia ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Sequencing Data ◽  
Childhood All ◽  
Exome Sequencing Data ◽  
Genome Wide ◽  
Whole Exome ◽  
Whole Exome Sequencing Data

Aim: To evaluate top-ranking genes identified through genome-wide association studies for an association with corticosteroid-related osteonecrosis in children with acute lymphoblastic leukemia (ALL) who received Dana–Farber Cancer Institute treatment protocols. Patients & methods: Lead SNPs from these studies, as well as other variants in the same genes, pooled from whole exome sequencing data, were analyzed for an association with osteonecrosis in childhood ALL patients from Quebec cohort. Top-ranking variants were verified in the replication patient group. Results: The analyses of variants in the ACP1-SH3YL1 locus derived from whole exome sequencing data showed an association of several correlated SNPs (rs11553746, rs2290911, rs7595075, rs2306060 and rs79716074). The rs79716074 defines *B haplotype of the APC1 gene, which is well known for its functional role. Conclusion: This study confirms implication of the ACP1 gene in the treatment-related osteonecrosis in childhood ALL and identifies novel, potentially causal variant of this complication.

Sign in / Sign up

Export Citation Format

Share Document