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

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.

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

eLife ◽

10.7554/elife.37110 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 14

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.

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The FAM171A2 gene is a key regulator of progranulin expression and modifies the risk of multiple neurodegenerative diseases

Science Advances ◽

10.1126/sciadv.abb3063 ◽

2020 ◽

Vol 6 (43) ◽

pp. eabb3063

Author(s):

Wei Xu ◽

Si-Da Han ◽

Can Zhang ◽

Jie-Qiong Li ◽

Yan-Jiang Wang ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Genome Wide Association Study ◽

In Vitro Study ◽

Genome Wide ◽

A Genome ◽

Increased Risk ◽

Pathophysiological Role ◽

Independent Cohort

Progranulin (PGRN) is a secreted pleiotropic glycoprotein associated with the development of common neurodegenerative diseases. Understanding the pathophysiological role of PGRN may help uncover biological underpinnings. We performed a genome-wide association study to determine the genetic regulators of cerebrospinal fluid (CSF) PGRN levels. Common variants in region of FAM171A2 were associated with lower CSF PGRN levels (rs708384, P = 3.95 × 10−12). This was replicated in another independent cohort. The rs708384 was associated with increased risk of Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia and could modify the expression of the FAM171A2 gene. FAM171A2 was considerably expressed in the vascular endothelium and microglia, which are rich in PGRN. The in vitro study further confirmed that the rs708384 mutation up-regulated the expression of FAM171A2, which caused a decrease in the PGRN level. Collectively, genetic, molecular, and bioinformatic findings suggested that FAM171A2 is a key player in regulating PGRN production.

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Genomic and functional gene studies suggest a key role of beta-carotene oxygenase 1 like (bco1l) gene in salmon flesh color

10.1101/821652 ◽

2019 ◽

Author(s):

Hanna Helgeland ◽

Marte Sodeland ◽

Nina Zoric ◽

Jacob Seilø Torgersen ◽

Fabian Grammes ◽

...

Keyword(s):

Genome Wide Association Study ◽

Beta Carotene ◽

Color Variation ◽

Flesh Color ◽

Functional Studies ◽

Genetic Components ◽

Genome Wide ◽

A Genome ◽

Mrna And Protein Expression

AbstractRed coloration of muscle tissue (flesh) is a unique trait in several salmonid genera, including Atlantic salmon. The color results from dietary carotenoids deposited in the flesh, whereas the color intensity is affected both by diet and genetic components. Herein we report on a genome-wide association study (GWAS) to identify genetic variation underlying this trait. Two SNPs on ssa26 showed strong associations to the flesh color in salmon. Two genes known to be involved in carotenoid metabolism were located in this QTL-region: beta-carotene oxygenase 1 (bco1) and beta-carotene oxygenase 1 like (bco1l). To determine whether flesh color variation is caused by one, or both, of these genes, several functional studies were carried out including mRNA and protein expression in fish with red and pale flesh color. The catalytic abilities of these two genes were also tested with different carotenoids. Our results suggest bco1l to be the most likely gene to explain the flesh color variation observed in this population.

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Genomic and functional gene studies suggest a key role of beta-carotene oxygenase 1 like (bco1l) gene in salmon flesh color

Scientific Reports ◽

10.1038/s41598-019-56438-3 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Hanna Helgeland ◽

Marte Sodeland ◽

Nina Zoric ◽

Jacob Seilø Torgersen ◽

Fabian Grammes ◽

...

Keyword(s):

Genome Wide Association Study ◽

Beta Carotene ◽

Color Variation ◽

Flesh Color ◽

Functional Studies ◽

Genetic Components ◽

Genome Wide ◽

A Genome ◽

Mrna And Protein Expression

AbstractRed coloration of muscle tissue (flesh) is a unique trait in several salmonid genera, including Atlantic salmon. The color results from dietary carotenoids deposited in the flesh, whereas the color intensity is affected both by diet and genetic components. Herein we report on a genome-wide association study (GWAS) to identify genetic variation underlying this trait. Two SNPs on ssa26 showed strong associations to the flesh color in salmon. Two genes known to be involved in carotenoid metabolism were located in this QTL- region: beta-carotene oxygenase 1 (bco1) and beta-carotene oxygenase 1 like (bco1l). To determine whether flesh color variation is caused by one, or both, of these genes, functional studies were carried out including mRNA and protein expression in fish with red and pale flesh color. The catalytic abilities of these two genes were also tested with different carotenoids. Our results suggest bco1l to be the most likely gene to explain the flesh color variation observed in this population.

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Whole genome sequencing identified a 16 kilobase deletion on ECA13 associated with distichiasis in Friesian horses

BMC Genomics ◽

10.1186/s12864-020-07265-8 ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

E. A. Hisey ◽

H. Hermans ◽

Z. T. Lounsberry ◽

F. Avila ◽

R. A. Grahn ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Genome Wide Association Study ◽

Secondary Infection ◽

Whole Genome Sequencing Data ◽

Incomplete Penetrance ◽

Whole Genome ◽

Genome Wide ◽

A Genome

Abstract Background Distichiasis, an ocular disorder in which aberrant cilia (eyelashes) grow from the opening of the Meibomian glands of the eyelid, has been reported in Friesian horses. These misplaced cilia can cause discomfort, chronic keratitis, and corneal ulceration, potentially impacting vision due to corneal fibrosis, or, if secondary infection occurs, may lead to loss of the eye. Friesian horses represent the vast majority of reported cases of equine distichiasis, and as the breed is known to be affected with inherited monogenic disorders, this condition was hypothesized to be a simply inherited Mendelian trait. Results A genome wide association study (GWAS) was performed using the Axiom 670 k Equine Genotyping array (MNEc670k) utilizing 14 cases and 38 controls phenotyped for distichiasis. An additive single locus mixed linear model (EMMAX) approach identified a 1.83 Mb locus on ECA5 and a 1.34 Mb locus on ECA13 that reached genome-wide significance (pcorrected = 0.016 and 0.032, respectively). Only the locus on ECA13 withstood replication testing (p = 1.6 × 10− 5, cases: n = 5 and controls: n = 37). A 371 kb run of homozygosity (ROH) on ECA13 was found in 13 of the 14 cases, providing evidence for a recessive mode of inheritance. Haplotype analysis (hapQTL) narrowed the region of association on ECA13 to 163 kb. Whole-genome sequencing data from 3 cases and 2 controls identified a 16 kb deletion within the ECA13 associated haplotype (ECA13:g.178714_195130del). Functional annotation data supports a tissue-specific regulatory role of this locus. This deletion was associated with distichiasis, as 18 of the 19 cases were homozygous (p = 4.8 × 10− 13). Genotyping the deletion in 955 horses from 54 different breeds identified the deletion in only 11 non-Friesians, all of which were carriers, suggesting that this could be causal for this Friesian disorder. Conclusions This study identified a 16 kb deletion on ECA13 in an intergenic region that was associated with distichiasis in Friesian horses. Further functional analysis in relevant tissues from cases and controls will help to clarify the precise role of this deletion in normal and abnormal eyelash development and investigate the hypothesis of incomplete penetrance.

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

The American Journal of Human Genetics ◽

10.1016/j.ajhg.2016.11.013 ◽

2017 ◽

Vol 100 (1) ◽

pp. 64-74 ◽

Cited By ~ 30

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

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Genome-Wide Significance for PCLO as a Gene for Major Depressive Disorder

Twin Research and Human Genetics ◽

10.1017/thg.2017.30 ◽

2017 ◽

Vol 20 (4) ◽

pp. 267-270 ◽

Cited By ~ 14

Author(s):

Hamdi Mbarek ◽

Yuri Milaneschi ◽

Jouke-Jan Hottenga ◽

Lannie Ligthart ◽

Eco J. C. de Geus ◽

...

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Genome Wide Association Study ◽

Major Depressive ◽

Significance Level ◽

Functional Studies ◽

Genome Wide ◽

A Genome ◽

Genome Wide Significance

In 2009, the first genome-wide association study (GWAS) for major depressive disorder (MDD) highlighted an association with PCLO locus on chromosome 7, although not reaching genome-wide significance level. In the present study, we revisited the original GWAS after increasing the overall sample size and the number of interrogated SNPs. In an analysis comparing 1,942 cases with lifetime diagnosis of MDD and 4,565 controls, PCLO showed a genome-wide significant association with MDD at SNP (rs2715157, p = 2.91 × 10−8) and gene-based (p = 1.48 × 10−7) level. Our results confirm the potential role of the PCLO gene in MDD, which is worth further replication and functional studies.

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Integrative genomic analyses identify susceptibility genes underlying COVID-19 hospitalization

Nature Communications ◽

10.1038/s41467-021-24824-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Gita A. Pathak ◽

Kritika Singh ◽

Tyne W. Miller-Fleming ◽

Frank R. Wendt ◽

Nava Ehsan ◽

...

Keyword(s):

Genome Wide Association Study ◽

Clinical Symptoms ◽

Ethnic Studies ◽

Host Genetics ◽

Protein Levels ◽

Genome Wide ◽

A Genome ◽

Causal Genes ◽

Host Inflammatory Response

AbstractDespite rapid progress in characterizing the role of host genetics in SARS-Cov-2 infection, there is limited understanding of genes and pathways that contribute to COVID-19. Here, we integrate a genome-wide association study of COVID-19 hospitalization (7,885 cases and 961,804 controls from COVID-19 Host Genetics Initiative) with mRNA expression, splicing, and protein levels (n = 18,502). We identify 27 genes related to inflammation and coagulation pathways whose genetically predicted expression was associated with COVID-19 hospitalization. We functionally characterize the 27 genes using phenome- and laboratory-wide association scans in Vanderbilt Biobank (n = 85,460) and identified coagulation-related clinical symptoms, immunologic, and blood-cell-related biomarkers. We replicate these findings across trans-ethnic studies and observed consistent effects in individuals of diverse ancestral backgrounds in Vanderbilt Biobank, pan-UK Biobank, and Biobank Japan. Our study highlights and reconfirms putative causal genes impacting COVID-19 severity and symptomology through the host inflammatory response.

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

10.1101/2020.07.19.20153841 ◽

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.

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