scholarly journals Exome sequencing of 457 autism families recruited online provides evidence for novel ASD genes

2019 ◽  
Author(s):  
Pamela Feliciano ◽  
Xueya Zhou ◽  
Irina Astrovskaya ◽  
Tychele N. Turner ◽  
Tianyun Wang ◽  
...  
Keyword(s):  
Risk Factors ◽  
Exome Sequencing ◽  
Genetic Risk ◽  
De Novo ◽  
Meta Analysis ◽  
Genetic Risk Factors ◽  
Autism Spectrum ◽  
Whole Exome ◽  
Statistical Support ◽  
Complete Set

Autism spectrum disorder (ASD) is a genetically heterogeneous condition, caused by a combination of rare de novo and inherited variants as well as common variants in at least several hundred genes. However, significantly larger sample sizes are needed to identify the complete set of genetic risk factors. We conducted a pilot study for SPARK (SPARKForAutism.org) of 457 families with ASD, all consented online. Whole exome sequencing (WES) and genotyping data were generated for each family using DNA from saliva. We identified variants in genes and loci that are clinically recognized causes or significant contributors to ASD in 10.4% of families without previous genetic findings. Additionally, we identified variants that are possibly associated with autism in an additional 3.4% of families. A meta-analysis using the TADA framework at a false discovery rate (FDR) of 0.2 provides statistical support for 34 ASD risk genes with at least one damaging variant identified in SPARK. Nine of these genes (BRSK2, DPP6, EGR3, FEZF2, ITSN1, KDM1B, NR4A2, PAX5 and RALGAPB) are newly emerging genes in autism, of which BRSK2 has the strongest statistical support as a risk gene for autism (TADA q-value = 0.0015). Future studies leveraging the thousands of individuals with ASD that have enrolled in SPARK are likely to further clarify the genetic risk factors associated with ASD as well as allow accelerate autism research that incorporates genetic etiology.

scholarly journals Whole-exome sequencing identified genetic risk factors for asparaginase-related complications in childhood ALL patients

Oncotarget ◽  
2017 ◽  
Vol 8 (27) ◽  
pp. 43752-43767 ◽  
Author(s):  
Rachid Abaji ◽  
Vincent Gagné ◽  
Chang Jiang Xu ◽  
Jean-François Spinella ◽  
Francesco Ceppi ◽  
...  
Keyword(s):  
Risk Factors ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Risk ◽  
Genetic Risk Factors ◽  
Childhood All ◽  
Whole Exome

Genetic Risk Factors for the Development of Osteonecrosis in Children Under Age 10 Treated for Acute Lymphoblastic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 250-250
Author(s):  
Seth E. Karol ◽  
Wenjian Yang ◽  
Leonard A. Mattano ◽  
Kelly W. Maloney ◽  
Colton Smith ◽  
...  
Keyword(s):  
Risk Factors ◽  
Glutamate Receptor ◽  
Genetic Risk ◽  
Lymphoblastic Leukemia ◽  
Meta Analysis ◽  
Genetic Risk Factors ◽  
Discovery Cohort ◽  
Genome Wide ◽  
Whole Exome ◽  
Manhattan Plot

Abstract Background: Therapy induced osteonecrosis has become a limiting toxicity in the intensification of treatment for pediatric acute lymphoblastic leukemia (ALL), particularly among patients 10 to 20 years of age. Prior studies on the genetic determinants of osteonecrosis have focused primarily on patients older than 10 years, leaving the genetic risk factors for the larger group of children with ALL less than 10 years old incompletely understood. It is hypothesized that genetic risk factors may account for a greater proportion of risk of osteonecrosis or involve differing mechanisms in younger than in older patients. Methods: We performed the first evaluation of genetic risk factors for osteonecrosis in children less than 10 years old using a discovery cohort of 82 cases of osteonecrosis and 287 controls treated on Children's Oncology Group (COG) protocol AALL0331 (NCI standard risk ALL) and tested for replication in 817 children less than 10 treated on COG protocol AALL0232 (high risk ALL). Genotyping was performed using the Affymetrix Gene Chip Human Mapping Array 6.0 and the Illumina Human Exome BeadChip v1.1. A subset of 15 cases in the discovery cohort had coding variant calls verified by whole exome sequencing. Both discovery and replication genome-wide association studies (GWAS) adjusted for demographic and therapy variables known to modify the risk of osteonecrosis. Enhancer enrichment analysis using HaploReg identified tissues affected by the identified single nucleotide polymorphisms (SNPs). Genes associated with the identified SNPs were evaluated using Ingenuity Pathway Analysis for enrichment in biologically relevant pathways. Results: Within the discovery cohort, top ranked variants were rs76599360 and rs77556622 which were in full linkage disequilibrium [P=1.13x10-9, odds ratio (OR) 22.0, 95% confidence interval (95%CI) 8.15-59.6] located near bone morphogenic protein 7 (BMP7). The top replicated SNPs were located near BMP7 [rs75161997, P=5.34x10-8 (OR 15.0; 95%CI 5.64-39.7) and P =0.0498 (OR 8.44; 95%CI 1.002-71.1) in the discovery and replication cohorts, respectively] and PROX1-antisense RNA1 [PROX1-AS1:rs1891059, P=2.28x10-7 (OR 6.48; 95%CI 3.19-13.1) and P=0.0077 (OR 3.78; 95%CI 1.42-10.1) for the discovery and replication cohorts, respectively]. The top replicated non-synonymous SNP, rs34144324, was in a glutamate receptor gene [GRID2, P=8.65x10-6 (OR 3.46; 95%CI 2.00-5.98) and 0.0136 (OR 10.8; 95%CI 1.63-71.4) in the discovery and replication cohorts, respectively], and the genotyping of this variant was verified in the whole exome sequencing data. In a meta-analysis of both cohorts, the replicated BMP7 and PROX1-AS1 variants (rs75161997 and rs1891059, respectively) and a variant in NCRNA00251 (rs141059755) met the genome-wide significance threshold of <5x10-8 (Figure 1). In a meta-analysis of both cohorts, replicated SNPs with meta-analysis P<1 x10-5 showed enrichment in enhancers active in mesenchymal stem cells. Pathway analysis of genes linked to top SNPs (meta-analysis P <0.001) demonstrated enrichment in glutamate receptor signaling and adipogenesis pathways. Conclusions: Variants in genes important to bone and fat differentiation from mesenchymal stem cells were associated with osteonecrosis in children less than 10 years old. The importance of variants in glutamate receptor signaling in children less than 10 also confirms the findings of a recently completed GWAS of osteonecrosis in AALL0232 (Blood 2014 124:367; 2014) including patients of all ages and in which osteonecrosis occurred primarily in older children. These data provide new insights into osteonecrosis with implications for patients of all ages. Figure 1. Manhattan plot of meta-analysis for osteonecrosis risk in children <10 years old Figure 1. Manhattan plot of meta-analysis for osteonecrosis risk in children <10 years old Disclosures Hunger: Sigma Tau: Consultancy; Jazz Pharmaceuticals: Consultancy; Merck: Equity Ownership; Spectrum Pharmaceuticals: Consultancy.

scholarly journals Identification of potential genetic risk factors for bipolar disorder by whole-exome sequencing

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Thomas Husson ◽  
◽  
Jean-Baptiste Duboc ◽  
Olivier Quenez ◽  
Camille Charbonnier ◽  
...  
Keyword(s):  
Risk Factors ◽  
Bipolar Disorder ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Risk ◽  
Genetic Risk Factors ◽  
Whole Exome

scholarly journals Whole exome sequencing in thrombophilic pedigrees to identify genetic risk factors for venous thromboembolism

PLoS ONE ◽  
2017 ◽  
Vol 12 (11) ◽  
pp. e0187699 ◽  
Author(s):  
Marisa L. R. Cunha ◽  
Joost C. M. Meijers ◽  
Frits R. Rosendaal ◽  
Astrid van Hylckama Vlieg ◽  
Pieter H. Reitsma ◽  
...  
Keyword(s):  
Risk Factors ◽  
Venous Thromboembolism ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Risk ◽  
Genetic Risk Factors ◽  
Whole Exome

scholarly journals Whole-Exome Sequencing Identifies SLC52A1 and ZNF106 Variants as Novel Genetic Risk Factors for (Early) Multiple-Organ Failure in Acute Pancreatitis

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Fons F. van den Berg ◽  
Yama Issa ◽  
Jeroen P. Vreijling ◽  
Markus M. Lerch ◽  
Frank Ulrich Weiss ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Pancreatitis ◽  
Multiple Organ Failure ◽  
Organ Failure ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Risk ◽  
Genetic Risk Factors ◽  
Multiple Organ ◽  
Whole Exome

scholarly journals Integrating de novo and inherited variants in over 42,607 autism cases identifies mutations in new moderate risk genes

2021 ◽  
Author(s):  
Xueya Zhou ◽  
Pamela Feliciano ◽  
Tianyun Wang ◽  
Irina Astrovskaya ◽  
Chang Shu ◽  
...  
Keyword(s):  
Genetic Risk ◽  
De Novo ◽  
Meta Analysis ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Moderate Risk ◽  
Full Spectrum ◽  
Risk Genes ◽  
Biological Parents

AbstractDespite the known heritable nature of autism spectrum disorder (ASD), studies have primarily identified risk genes with de novo variants (DNVs). To capture the full spectrum of ASD genetic risk, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases recruited online by SPARK. In the first stage, we analyzed 19,843 cases with one or both biological parents and found that known ASD or neurodevelopmental disorder (NDD) risk genes explain nearly 70% of the genetic burden conferred by DNVs. In contrast, less than 20% of genetic risk conferred by rare inherited loss-of-function (LoF) variants are explained by known ASD/NDD genes. We selected 404 genes based on the first stage of analysis and performed a meta-analysis with an additional 22,764 cases and 236,000 population controls. We identified 60 genes with exome-wide significance (p < 2.5e-6), including five new risk genes (NAV3, ITSN1, MARK2, SCAF1, and HNRNPUL2). The association of NAV3 with ASD risk is entirely driven by rare inherited LoFs variants, with an average relative risk of 4, consistent with moderate effect. ASD individuals with LoF variants in the four moderate risk genes (NAV3, ITSN1, SCAF1, and HNRNPUL2, n = 95) have less cognitive impairment compared to 129 ASD individuals with LoF variants in well-established, highly penetrant ASD risk genes (CHD8, SCN2A, ADNP, FOXP1, SHANK3) (59% vs. 88%, p= 1.9e-06). These findings will guide future gene discovery efforts and suggest that much larger numbers of ASD cases and controls are needed to identify additional genes that confer moderate risk of ASD through rare, inherited variants.

scholarly journals Possible Endophenotypes in the Search for Genetic Risk Factors in Autism Spectrum Disorders

10.5772/60039 ◽  
2015 ◽  
Author(s):  
Adriana Díaz-Anzaldúa ◽  
Rigoberto Rosendo Gutiérrez ◽  
Alejandro Díaz-Anzaldúa ◽  
José Octavio Hernández Lagunas
Keyword(s):  
Risk Factors ◽  
Autism Spectrum Disorders ◽  
Genetic Risk ◽  
Genetic Risk Factors ◽  
Autism Spectrum ◽  
Spectrum Disorders
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