scholarly journals Genetic predisposition to uterine leiomyoma is determined by loci for genitourinary development and genome stability

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Niko Välimäki ◽  
Heli Kuisma ◽  
Annukka Pasanen ◽  
Oskari Heikinheimo ◽  
Jari Sjöberg ◽  
...  
Keyword(s):  
Genome Stability ◽  
Genome Wide Association Study ◽  
Telomere Maintenance ◽  
Stem Cell Marker ◽  
Benign Tumors ◽  
Risk Alleles ◽  
Genome Wide ◽  
A Genome ◽  
Predisposition Genes ◽  
Marker Antigen

Uterine leiomyomas (ULs) are benign tumors that are a major burden to women’s health. A genome-wide association study on 15,453 UL cases and 392,628 controls was performed, followed by replication of the genomic risk in six cohorts. Effects of the risk alleles were evaluated in view of molecular and clinical characteristics. 22 loci displayed a genome-wide significant association. The likely predisposition genes could be grouped to two biological processes. Genes involved in genome stability were represented by TERT, TERC, OBFC1 - highlighting the role of telomere maintenance - TP53 and ATM. Genes involved in genitourinary development, WNT4, WT1, SALL1, MED12, ESR1, GREB1, FOXO1, DMRT1 and uterine stem cell marker antigen CD44, formed another strong subgroup. The combined risk contributed by the 22 loci was associated with MED12 mutation-positive tumors. The findings link genes for uterine development and genetic stability to leiomyomagenesis, and in part explain the more frequent occurrence of UL in women of African origin.

scholarly journals ESR1, WT1, WNT4, ATM and TERT loci are major contributors to uterine leiomyoma predisposition

2018 ◽  
Author(s):  
Niko Välimäki ◽  
Heli Kuisma ◽  
Annukka Pasanen ◽  
Oskari Heikinheimo ◽  
Jari Sjöberg ◽  
...  
Keyword(s):  
Estrogen Receptor Alpha ◽  
Genome Wide Association Study ◽  
Benign Tumors ◽  
Risk Alleles ◽  
Estrogen Exposure ◽  
Genome Wide ◽  
A Genome ◽  
Genetic Level ◽  
Genomic Risk

ABSTRACTUterine leiomyomas (ULs) are benign tumors that are a major burden to women’s health. A genome-wide association study on 5,417 UL cases and 331,791 controls was performed, followed by replication of the genomic risk in two cohorts. Effects of the identified risk alleles were evaluated in view of molecular and clinical features.Five loci displayed a genome-wide significant association; the previously reported TNRC6B, and four novel loci ESR1 (ERα), WT1, WNT4, and ATM. The sixth hit TERT is also a conceivable target. The combined polygenic risk contributed by these loci was associated with MED12 mutation-positive tumors. The findings link genes for uterine development and genetic stability to leiomyomagenesis. While the fundamental role of sex hormones in UL aetiology has been clear, this work reveals a connection to estrogen receptor alpha on genetic level and suggests that determinants of UL growth associated with estrogen exposure have an inherited component.

scholarly journals A Genome-wide Association Study Identifies Risk Alleles in Plasminogen and P4HA2 Associated with Giant Cell Arteritis

2017 ◽  
Vol 100 (1) ◽  
pp. 64-74 ◽  
Author(s):  
F. David Carmona ◽  
Augusto Vaglio ◽  
Sarah L. Mackie ◽  
José Hernández-Rodríguez ◽  
Paul A. Monach ◽  
...  
Keyword(s):  
Association Study ◽  
Giant Cell Arteritis ◽  
Giant Cell ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Risk Alleles ◽  
Genome Wide ◽  
A Genome

scholarly journals Multiethnic genome-wide association study of differentiated thyroid cancer in the EPITHYR consortium

2020 ◽  
Author(s):  
Therese TRUONG ◽  
Fabienne Lesueur ◽  
Pierre-emmanuel Sugier ◽  
Julie Guibon ◽  
Constance Xhaard ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Differentiated Thyroid Carcinoma ◽  
Incidence Rates ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Risk Alleles ◽  
Genome Wide ◽  
A Genome ◽  
High Incidence

Incidence of differentiated thyroid carcinoma (DTC) varies considerably between ethnic groups, with particularly high incidence rates in Pacific Islanders. Here, we conducted a genome-wide association study (GWAS) involving 1,554 cases/1,973 controls of European ancestry and 301 cases/348 controls of Oceanian ancestry from the EPITHYR consortium. Our results confirmed the association with the known DTC susceptibility loci at 2q35, 8p12, 9q22.33 and 14q13.3 in the European ancestry population and suggested two novel signals at 1p31.3 (rs334729) and 16q23.2 (rs16950982), which were associated with TSH levels in previous GWAS. We additionally replicated an association with 5p15.33 reported previously in Chinese and European populations. Except at 1p31.3, all associations were in the same direction in the population of Oceanian ancestry. The frequency of risk alleles at 2q35, 5p15.33 and 16q23.2 were significantly higher in Oceanians than in Europeans and may explain part of the highest DTC incidence observed in Oceanians.

scholarly journals Genome-wide association study across five cohorts identifies five novel loci associated with idiopathic pulmonary fibrosis

2021 ◽  
Author(s):  
Richard J Allen ◽  
Amy Stockwell ◽  
Justin M Oldham ◽  
Beatriz Guillen-Guio ◽  
Carlos Flores ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Telomere Maintenance ◽  
Survival Times ◽  
Genome Wide ◽  
A Genome ◽  
Lung Condition ◽  
Independent Replication

AbstractIdiopathic pulmonary fibrosis (IPF) is a chronic lung condition with poor survival times. We previously published a genome-wide meta-analysis of IPF risk across three studies with independent replication of associated variants in two additional studies. To maximise power and to generate more accurate effect size estimates, we performed a genome-wide meta-analysis across all five studies included in the previous IPF risk GWAS. We utilised the distribution of effect sizes across the five studies to assess the replicability of the results and identified five robust novel genetic association signals implicating mTOR signalling, telomere maintenance and spindle assembly genes in IPF risk.

scholarly journals Novel susceptibility variants at the ERG locus for childhood acute lymphoblastic leukemia in Hispanics

Blood ◽  
2019 ◽  
Vol 133 (7) ◽  
pp. 724-729 ◽  
Author(s):  
Maoxiang Qian ◽  
Heng Xu ◽  
Virginia Perez-Andreu ◽  
Kathryn G. Roberts ◽  
Hui Zhang ◽  
...  
Keyword(s):  
Native American ◽  
Acute Lymphoblastic Leukemia ◽  
Genome Wide Association Study ◽  
Lymphoblastic Leukemia ◽  
Causal Variant ◽  
Risk Alleles ◽  
Genome Wide ◽  
A Genome ◽  
Dna Elements ◽  
Regulatory Dna

Abstract Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Characterized by high levels of Native American ancestry, Hispanics are disproportionally affected by this cancer with high incidence and inferior survival. However, the genetic basis for this disparity remains poorly understood because of a paucity of genome-wide investigation of ALL in Hispanics. Performing a genome-wide association study (GWAS) in 940 Hispanic children with ALL and 681 ancestry-matched non-ALL controls, we identified a novel susceptibility locus in the ERG gene (rs2836365; P = 3.76 × 10−8; odds ratio [OR] = 1.56), with independent validation (P = .01; OR = 1.43). Imputation analyses pointed to a single causal variant driving the association signal at this locus overlapping with putative regulatory DNA elements. The effect size of the ERG risk variant rose with increasing Native American genetic ancestry. The ERG risk genotype was underrepresented in ALL with the ETV6-RUNX1 fusion (P < .0005) but enriched in the TCF3-PBX1 subtype (P < .05). Interestingly, ALL cases with germline ERG risk alleles were significantly less likely to have somatic ERG deletion (P < .05). Our results provide novel insights into genetic predisposition to ALL and its contribution to racial disparity in this cancer.

scholarly journals Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia

2016 ◽  
Vol 22 (10) ◽  
pp. 1502-1508 ◽  
Author(s):  
S E Legge ◽  
◽  
M L Hamshere ◽  
S Ripke ◽  
A F Pardinas ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Human Leukocyte ◽  
Risk Alleles ◽  
Rare Variant Analysis ◽  
Genome Wide ◽  
A Genome ◽  
Novel Association ◽  
Number Variation ◽  
Hepatic Transporter

Abstract The antipsychotic clozapine is uniquely effective in the management of schizophrenia; however, its use is limited by its potential to induce agranulocytosis. The causes of this, and of its precursor neutropenia, are largely unknown, although genetic factors have an important role. We sought risk alleles for clozapine-associated neutropenia in a sample of 66 cases and 5583 clozapine-treated controls, through a genome-wide association study (GWAS), imputed human leukocyte antigen (HLA) alleles, exome array and copy-number variation (CNV) analyses. We then combined associated variants in a meta-analysis with data from the Clozapine-Induced Agranulocytosis Consortium (up to 163 cases and 7970 controls). In the largest combined sample to date, we identified a novel association with rs149104283 (odds ratio (OR)=4.32, P=1.79 × 10−8), intronic to transcripts of SLCO1B3 and SLCO1B7, members of a family of hepatic transporter genes previously implicated in adverse drug reactions including simvastatin-induced myopathy and docetaxel-induced neutropenia. Exome array analysis identified gene-wide associations of uncommon non-synonymous variants within UBAP2 and STARD9. We additionally provide independent replication of a previously identified variant in HLA-DQB1 (OR=15.6, P=0.015, positive predictive value=35.1%). These results implicate biological pathways through which clozapine may act to cause this serious adverse effect.

scholarly journals Genome-wide association study of over 40,000 bipolar disorder cases provides novel biological insights

2020 ◽  
Author(s):  
Niamh Mullins ◽  
Andreas J Forstner ◽  
Kevin S O'Connell ◽  
Brandon Coombes ◽  
Jonathan R I Coleman ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Association Study ◽  
Genome Wide Association Study ◽  
High Specificity ◽  
Genome Wide Association ◽  
Channel Blockers ◽  
Risk Alleles ◽  
Genome Wide ◽  
A Genome ◽  
Polygenic Scores

Bipolar disorder (BD) is a heritable mental illness with complex etiology. We performed a genome-wide association study (GWAS) of 41,917 BD cases and 371,549 controls, which identified 64 associated genomic loci. BD risk alleles were enriched in genes in synaptic and calcium signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers and antiepileptics. Integrating eQTL data implicated 15 genes robustly linked to BD via gene expression, including druggable genes such as HTR6, MCHR1, DCLK3 and FURIN. This GWAS provides the best-powered BD polygenic scores to date, when applied in both European and diverse ancestry samples. Together, these results advance our understanding of the biological etiology of BD, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

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