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

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.

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Genetic Analysis of Osteoblast Activity Identifies Zbtb40 as a Regulator of Osteoblast Activity and Bone Mass

10.1101/828525 ◽

2019 ◽

Author(s):

Madison L. Doolittle ◽

Gina M Calabrese ◽

Larry D. Mesner ◽

Dana A. Godfrey ◽

Robert D. Maynard ◽

...

Keyword(s):

Bone Formation ◽

Genetic Basis ◽

Association Studies ◽

Genome Wide Association Studies ◽

Loss Of Function ◽

Mineral Density ◽

Osteoblast Activity ◽

Genome Wide ◽

Increased Risk

ABSTRACTOsteoporosis is a genetic disease characterized by progressive reductions in bone mineral density (BMD) leading to an increased risk of fracture. Over the last decade, genome-wide association studies (GWASs) have identified over 1000 associations for BMD. However, as a phenotype BMD is challenging as bone is a multicellular tissue affected by both local and systemic physiology. Here, we focused on a single component of BMD, osteoblast-mediated bone formation in mice, and identified associations influencing osteoblast activity on mouse Chromosomes (Chrs) 1, 4, and 17. The locus on Chr. 4 was in an intergenic region between Wnt4 and Zbtb40, homologous to a locus for BMD in humans. We tested both Wnt4 and Zbtb40 for a role in osteoblast activity and BMD. Knockdown of Zbtb40, but not Wnt4, in osteoblasts drastically reduced mineralization. Additionally, loss-of-function mouse models for both genes exhibited reduced BMD. Our results highlight that investigating the genetic basis of in vitro osteoblast mineralization can be used to identify genes impacting bone formation and BMD.

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Genome-wide association study of circulating liver enzymes reveals an expanded role for manganese transporter SLC30A10 in liver health

10.1101/2020.05.19.104570 ◽

2020 ◽

Author(s):

Lucas D. Ward ◽

Ho-Chou Tu ◽

Chelsea Quenneville ◽

Alexander O. Flynn-Carroll ◽

Margaret M. Parker ◽

...

Keyword(s):

Extrahepatic Bile Duct ◽

Association Studies ◽

Genome Wide Association ◽

Detectable Effect ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

Extrahepatic Bile Duct Cancer ◽

Genome Wide ◽

Liver Health ◽

The Uk

AbstractTo better understand molecular pathways underlying liver health and disease, we performed genome-wide association studies (GWAS) on circulating levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) across 408,300 subjects from four ethnic groups in the UK Biobank, focusing on variants associating with both enzymes. Of these variants, the strongest effect is a rare (MAF in White British = 0.12%) missense variant in the gene encoding manganese efflux transporter SLC30A10, Thr95Ile (rs188273166), associating with a 5.9% increase in ALT and a 4.2% increase in AST. Carriers have higher prevalence of all-cause liver disease (OR = 1.70; 95% CI = 1.24 to 2.34) and higher prevalence of extrahepatic bile duct cancer (OR = 23.8; 95% CI = 9.1 to 62.1) compared to non-carriers. Over 4% of the cases of extrahepatic cholangiocarcinoma in the UK Biobank carry SLC30A10 Thr95Ile. Unlike variants in SLC30A10 known to cause the recessive syndrome hypermanganesemia with dystonia-1 (HMNDYT1), the Thr95Ile variant has a detectable effect even in the heterozygous state. Also unlike HMNDYT1-causing variants, Thr95Ile results in a protein that is properly trafficked to the plasma membrane when expressed in HeLa cells. These results suggest that coding variation in SLC30A10 impacts liver health in more individuals than the small population of HMNDYT1 patients.

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A missense variant in SHARPIN mediates Alzheimer’s disease-specific brain damages

Translational Psychiatry ◽

10.1038/s41398-021-01680-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jun Young Park ◽

Dongsoo Lee ◽

Jang Jae Lee ◽

Jungsoo Gim ◽

Tamil Iniyan Gunasekaran ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cortical Thickness ◽

Association Studies ◽

Brain Magnetic Resonance Imaging ◽

Amyloid Β ◽

Missense Variant ◽

Hippocampal Volume ◽

Genome Wide Association Studies ◽

Increased Risk

AbstractEstablished genetic risk factors for Alzheimer’s disease (AD) account for only a portion of AD heritability. The aim of this study was to identify novel associations between genetic variants and AD-specific brain atrophy. We conducted genome-wide association studies for brain magnetic resonance imaging measures of hippocampal volume and entorhinal cortical thickness in 2643 Koreans meeting the clinical criteria for AD (n = 209), mild cognitive impairment (n = 1449) or normal cognition (n = 985). A missense variant, rs77359862 (R274W), in the SHANK-associated RH Domain Interactor (SHARPIN) gene was associated with entorhinal cortical thickness (p = 5.0 × 10−9) and hippocampal volume (p = 5.1 × 10−12). It revealed an increased risk of developing AD in the mediation analyses. This variant was also associated with amyloid-β accumulation (p = 0.03) and measures of memory (p = 1.0 × 10−4) and executive function (p = 0.04). We also found significant association of other SHARPIN variants with hippocampal volume in the Alzheimer’s Disease Neuroimaging Initiative (rs3417062, p = 4.1 × 10−6) and AddNeuroMed (rs138412600, p = 5.9 × 10−5) cohorts. Further, molecular dynamics simulations and co-immunoprecipitation indicated that the variant significantly reduced the binding of linear ubiquitination assembly complex proteins, SHPARIN and HOIL-1 Interacting Protein (HOIP), altering the downstream NF-κB signaling pathway. These findings suggest that SHARPIN plays an important role in the pathogenesis of AD.

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Loss-of-Function Variants in Cytoskeletal Genes Are Associated with Early-Onset Atrial Fibrillation

Journal of Clinical Medicine ◽

10.3390/jcm9020372 ◽

2020 ◽

Vol 9 (2) ◽

pp. 372 ◽

Cited By ~ 1

Author(s):

Oliver Bundgaard Vad ◽

Christian Paludan-Müller ◽

Gustav Ahlberg ◽

Silje Madeleine Kalstø ◽

Jonas Ghouse ◽

...

Keyword(s):

Atrial Fibrillation ◽

Genetic Correlation ◽

Early Onset ◽

Association Studies ◽

Cytoskeletal Proteins ◽

Control Group ◽

Genome Wide Association Studies ◽

Loss Of Function ◽

Increased Risk ◽

Genes Encoding

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and it is associated with an increased risk of heart failure, stroke, dementia, and death. Recently, titin-truncating variants (TTNtv), which are predominantly associated with dilated cardiomyopathy (DCM), were associated with early-onset AF. Furthermore, genome-wide association studies (GWAS) associated AF with other structural genes. In this study, we investigated whether early-onset AF was associated with loss-of-function variants in DCM-associated genes encoding cytoskeletal proteins. Using targeted sequencing, we examined a cohort of 527 Scandinavian individuals with early-onset AF and a control group of individuals free of AF (n = 383). The patients had onset of AF before 50 years of age, normal echocardiogram, and no other cardiovascular disease at onset of AF. We identified six individuals with rare loss-of-function variants in three different genes (dystrophin (DMD), actin-associated LIM protein (PDLIM3), and fukutin (FKTN)), of which two variants were novel. Loss-of-function variants in cytoskeletal genes were significantly associated with early-onset AF when patients were compared with controls (p = 0.044). Using publicly available GWAS data, we performed genetic correlation analyses between AF and 13 other traits, e.g., showing genetic correlation between AF and non-ischemic cardiomyopathy (p = 0.0003). Our data suggest that rare loss-of-function variants in cytoskeletal genes previously associated with DCM may have a role in early-onset AF, perhaps through the development of an atrial cardiomyopathy.

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A Phenome-Wide Association Study of genes associated with COVID-19 severity reveals shared genetics with complex diseases in the Million Veteran Program

10.1101/2021.05.18.21257396 ◽

2021 ◽

Author(s):

Anurag Verma ◽

Noah L. Tsao ◽

Lauren O. Thomann ◽

Yuk-Lam Ho ◽

Rotonya Carr ◽

...

Keyword(s):

Association Study ◽

Genetic Variants ◽

Genetic Architecture ◽

Association Studies ◽

Missense Variant ◽

International Classification Of Diseases ◽

Genome Wide Association Studies ◽

Increased Risk ◽

Significant Difference ◽

Shared Genetic

Background There are certain pre-existing conditions which leads in increased risk of coronavirus disease 2019 (COVID-19) severity and mortality. The objective of this study is to determine shared genetic architecture between COVID-19 severity and other medical conditions using electronic health record (EHR) data from diverse patient populations. Methods and Findings: We conducted Phenome-wide association study (PheWAS) of genetic variants associated with severe COVID-19 in two biobanks with EHR and genomic data: 1) Veteran Affairs (VA) Million Veteran Program (MVP), 2) United Kingdom Biobank (UKBB). Genetic variants associated with critical illness (n=48) or hospitalization (n=39) due to COVID-19 from COVID-19 Host Genetics Initiative genome-wide association studies. Phenotypes defined by International Classification of Diseases (ICD) codes mapped to clinically relevant groups using published PheWAS methods; pre-COVID-19 data used to avoid potential confounding. Among 455,683 US Veterans from MVP, variants associated with severe COVID-19 tested for association across 1,559 phenotypes; 353,365 UK Biobank participants, and 1,064 phenotypes tested. Genetic variants at ABO locus (rs550057, rs505922) associated with the largest number of phenotypes (nrs55057= 53 and nrs505922=61); strongest association with venous embolism, odds ratio (OR)rs550057 1.27 (p=5.28 x 10-116), and thrombosis ORrs505922 1.31, p=3.5 x10-183. Among 67 respiratory conditions tested, only idiopathic pulmonary fibrosis, OR rs2277732 1.17, p=1.3410-05, and asthma ORrs143334143 0.94, p=2.31 x10-04, shared variants with severe COVID-19. The RAVER1 locus (rs74956615) associated with reduced risk for autoimmune conditions, e.g. psoriasis OR 0.71, p= 1.53 x10-22, rheumatoid arthritis, OR 0.78, p=1.04 x 10-09; findings replicated in UKBB. A known functional missense variant (rs34536443, TYK2) in the region had the highest linkage disequilibrium with rs74956615, suggesting signal was likely from TYK2. In MVP, PheWAS results stratified by genetic ancestry did not demonstrate significant difference in associations across ancestry. Conclusions Shared genetic architecture between COVID-19 severity and conditions related to underlying risk factors for severe and poor COVID-19 outcomes; associations similar across genetic ancestries. Divergent association between inflammatory conditions and severe COVID may be explained by known pathway impairing signaling of inflammatory cytokines, reducing risk for autoimmunity; same pathway reduces type 1 interferon signaling, critical for viral host defense. Caution needed when targeting pathways that may balance immune tolerance and immunodeficiency to treat COVID-19.

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Candidate Genes for Nonsyndromic Cleft Palate Detected by Exome Sequencing

Journal of Dental Research ◽

10.1177/0022034517722761 ◽

2017 ◽

Vol 96 (11) ◽

pp. 1314-1321 ◽

Cited By ~ 15

Author(s):

A.K. Hoebel ◽

D. Drichel ◽

M. van de Vorst ◽

A.C. Böhmer ◽

S. Sivalingam ◽

...

Keyword(s):

Cleft Palate ◽

Exome Sequencing ◽

Candidate Genes ◽

Rare Variants ◽

Association Studies ◽

Low Frequency ◽

Missense Variant ◽

Genome Wide Association Studies ◽

Loss Of Function ◽

Novel Variant

Nonsyndromic cleft palate only (nsCPO) is a facial malformation that has a livebirth prevalence of 1 in 2,500. Research suggests that the etiology of nsCPO is multifactorial, with a clear genetic component. To date, genome-wide association studies have identified only 1 conclusive common variant for nsCPO, that is, a missense variant in the gene grainyhead-like-3 ( GRHL3). Thus, the underlying genetic causes of nsCPO remain largely unknown. The present study aimed at identifying rare variants that might contribute to nsCPO risk, via whole-exome sequencing (WES), in multiply affected Central European nsCPO pedigrees. WES was performed in 2 affected first-degree relatives from each family. Variants shared between both individuals were analyzed for their potential deleterious nature and a low frequency in the general population. Genes carrying promising variants were annotated for 1) reported associations with facial development, 2) multiple occurrence of variants, and 3) expression in mouse embryonic palatal shelves. This strategy resulted in the identification of a set of 26 candidate genes that were resequenced in 132 independent nsCPO cases and 623 independent controls of 2 different ethnicities, using molecular inversion probes. No rare loss-of-function mutation was identified in either WES or resequencing step. However, we identified 2 or more missense variants predicted to be deleterious in each of 3 genes ( ACACB, PTPRS, MIB1) in individuals from independent families. In addition, the analyses identified a novel variant in GRHL3 in 1 patient and a variant in CREBBP in 2 siblings. Both genes underlie different syndromic forms of CPO. A plausible hypothesis is that the apparently nonsyndromic clefts in these 3 patients might represent hypomorphic forms of the respective syndromes. In summary, the present study identified rare variants that might contribute to nsCPO risk and suggests candidate genes for further investigation.

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Thrombotic risk determined by protein C receptor (PROCR) variants among middle-aged and older adults: a population-based cohort study

Thrombosis and Haemostasis ◽

10.1055/a-1738-1564 ◽

2022 ◽

Author(s):

Eric Manderstedt ◽

Christer Hallden ◽

Christina Lind-Hallden ◽

Johan Elf ◽

peter svensson ◽

...

Keyword(s):

Older Adults ◽

Protein C ◽

Association Studies ◽

Large Population ◽

Missense Variant ◽

Population Based ◽

Genome Wide Association Studies ◽

Loss Of Function ◽

Middle Aged ◽

Thrombotic Risk

Background: The protein C (PC) anticoagulant system has a key role in maintaining hemostatic balance. One missense (Ser219Gly) variant in the protein C receptor (PROCR) was associated with venous thromboembolism (VTE) in genome-wide association studies. Objectives: This study aimed to determine the thrombotic risk of rare and common PROCR variants in a large population-based cohort of middle-aged and older adults. Patients/Methods: The exonic sequence of PROCR was analyzed for the Ser219Gly variant and other qualifying variants in 28,794 subjects (born 1923-1950, 60% women) without previous VTE, who participated in the Malmö Diet and Cancer study (1991-1996). Incidence of VTE was followed up until 2018. Qualifying variants were defined as loss-of-function or non-benign (PolyPhen-2) missense variants with minor allele frequencies (MAF) < 0.1%. Results: Resequencing identified 36 PROCR variants in the study population (26,210 non-VTE exomes and 2584 VTE exomes), 11 synonymous, 22 missense and three loss-of-function variants. Kaplan-Meier analysis of the known Ser219Gly variant (rs867186) showed that homozygosity for this variant increased the risk of disease whereas heterozygosity showed no effect. Cox multivariate regression analysis revealed an adjusted hazard ratio of 1.5 (95%CI 1.1-2.0). Fifteen rare variants were classified as qualifying and were included in collapsing analysis (burden test and SKAT-O). They did not contribute to risk. However, a Arg113Cys missense variant (rs146420040; MAF=0.004) showed an increased VTE risk (HR=1.3; 95%CI 1.0-1.9). Conclusions: Homozygosity for the Ser219Gly variant and a previously identified functional PROCR variant (Arg113Cys) was associated with VTE. Other variants did not contribute to VTE.

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Role of ARHGAP29 nucleotide variants in the etiology of non-syndromic cleft lip with or without cleft palate.

Journal of Medical Science ◽

10.20883/medical.e414 ◽

2020 ◽

Vol 89 (2) ◽

pp. e414

Author(s):

Justyna Dąbrowska ◽

Barbara Biedziak ◽

Agnieszka Lasota ◽

Paweł P. Jagodziński ◽

Adrianna Mostowska

Keyword(s):

Cleft Palate ◽

Candidate Gene ◽

Cleft Lip ◽

Association Studies ◽

Missense Variant ◽

P Value ◽

Genome Wide Association Studies ◽

Polish Population ◽

Increased Risk ◽

Strong Candidate

Aim. Non-syndromic cleft lip with or without cleft palate (nsCL/P) is a common birth defect of complex and heterogeneous aetiology. Genome-wide association studies (GWAS) of nsCL/P have identified an association for the 1p22.1 chromosomal region, in which ARHGAP29 was suggested as a candidate gene. Thus, the current study aimed to determine the contribution of the common and rare ARHGAP29 nucleotide variants to the risk of nsCL/P in the Polish population. Material and Methods. In total,197 common nucleotide variants (SNVs) and 22 missense variants located within the ARHGAP29 locus at chromosome 1p22.1 were genotyped by SNV microarray. The study was conducted in 269 individuals with nsCL/P and 569 healthy individuals. Results. Statistical analysis revealed that 31 common nucleotide variants located at the ARHGAP29 locus were significantly associated with the increased risk of nsCL/P. The strongest individual SNV was rs2391467 with a p-value = 2.49E-06 (OR = 1.64, 95%CI: 1.34–2.02). Besides, one potentially deleterious missense variant (rs140877322, p. Arg348Leu) was identified in a single patient with nsCLP. Conclusion. These findings confirm ARHGAP29 as a strong candidate gene for nsCL/P, with both common and rare nucleotide variants of this gene involved in the aetiology of nsCL/P in the Polish population.

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Loss-of-Function Variants in the SYNPO2L Gene Are Associated With Atrial Fibrillation

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.650667 ◽

2021 ◽

Vol 8 ◽

Author(s):

Alexander Guldmann Clausen ◽

Oliver Bundgaard Vad ◽

Julie Husted Andersen ◽

Morten Salling Olesen

Keyword(s):

Atrial Fibrillation ◽

Cardiac Myocyte ◽

Association Studies ◽

Structural Development ◽

Genome Wide Association Studies ◽

Loss Of Function ◽

Genome Wide ◽

Increased Risk ◽

Rare Genetic Variants ◽

And Function

Multiple genome-wide association studies (GWAS) have identified numerous loci associated with atrial fibrillation (AF). However, the genes driving these associations and how they contribute to the AF pathogenesis remains poorly understood. To identify genes likely to be driving the observed association, we searched the FinnGen study consisting of 12,859 AF cases and 73,341 controls for rare genetic variants predicted to cause loss-of-function. A specific splice site variant was found in the SYNPO2L gene, located in an AF associated locus on chromosome 10. This variant was associated with an increased risk of AF with a relatively high odds ratio of 3.5 (p = 9.9 × 10−8). SYNPO2L is an important gene involved in the structural development and function of the cardiac myocyte and our findings thus support the recent suggestions that AF can present as atrial cardiomyopathy.

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Pharmacogenomics of antiplatelet drugs

Hematology ◽

10.1182/asheducation-2014.1.343 ◽

2014 ◽

Vol 2014 (1) ◽

pp. 343-347 ◽

Cited By ~ 1

Author(s):

Marc S. Sabatine ◽

Jessica L. Mega

Keyword(s):

Platelet Reactivity ◽

Association Studies ◽

Fold Increase ◽

Coronary Intervention ◽

Genome Wide Association Studies ◽

Loss Of Function ◽

P2y12 Inhibitors ◽

Increased Risk ◽

Cytochrome 450 ◽

The Impact

Abstract Clopidogrel, a platelet P2Y12 inhibitor, is one of the most widely prescribed drugs in cardiovascular medicine because it reduces ischemic and thrombotic complications. It is a prodrug requiring biotransformation into the active metabolite by the hepatic cytochrome 450 system, especially the CYP2C19 enzyme. Candidate gene studies and genome-wide association studies have identified loss-of-function CYP2C19 variants to be associated with a diminished pharmacologic response. Specifically, compared with noncarriers, carriers of at least one copy of a loss-of-function CYP2C19 allele have ∼30% lower levels of active clopidogrel metabolite and ∼25% relatively less platelet inhibition with clopidogrel. Moreover, in patients treated with clopidogrel predominantly for percutaneous coronary intervention, carriers of 1 or 2 CYP2C19 loss-of-function alleles are at increased risk for major adverse cardiovascular outcomes, with an ∼1.5-fold increase in the risk of cardiovascular death, myocardial infarction, or stroke as well as an ∼3-fold increase in risk for stent thrombosis. Tripling the dose of clopidogrel in carriers of a CYP2C19 loss-of-function allele can achieve on-treatment platelet reactivity comparable to that seen with the standard 75 mg dose in wild-type individuals, but the impact on clinical outcomes remains unknown. Alternatively, 2 third-generation P2Y12 inhibitors are available: prasugrel and ticagrelor. These drugs are superior to clopidogrel in reducing ischemic outcomes and are unaffected by CYP2C19 loss-of-function alleles.

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