Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes

Pazoki, Raha; Vujkovic, Marijana; Elliott, Joshua; Εvangelou, Εvangelos; Gill, Dipender; Ghanbari, Mohsen; Most, Peter J. van der; Pinto, Rui; Wielscher, Matthias; Farlik, Matthias; Zuber, Verena; Knegt, Robert J. de; Snieder, Harold; Uitterlinden, André G.; Lynch, Julie; Jiang, Xiyun; Said, Saredo; Kaplan, David E.; Lee, Kyung Min; Serper, Marina; Carr, Rotonya M.; Tsao, Philip S.; Atkinson, Stephen R.; Dehghan, Abbas; Tzoulaki, Ioanna; Ikram, M. Arfan; Herzig, Karl‐Heinz; Järvelin, Marjo‐Riitta; Alizadeh, Behrooz Z.; O’Donnell, Christopher J.; Saleheen, Danish; Voight, Benjamin F.; Chang, Kyong–Mi; Thursz, Mark; Elliott, Paul; Program, VA Million Veteran

doi:10.1038/s41467-021-22338-2

Cited by 78 publications

(62 citation statements)

References 53 publications

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“…Pazoki et al performed GWAS on serum levels of ALT, ALP, and GGT (n=437,438) and replicated their results in three additional cohorts (n=315,572) (87). These enzymatic indicators of inflammation and liver disease were associated with 517 SNPs, including variants in SERPINA1, APOE, GPAM, MARC1, and LEPR.…”

Section: Genetic Associations Discovered In the Past Four Yearsmentioning

confidence: 93%

“…GPAM, PPP1R3B, and APOE have associations with steatosis (84-86, 88, 93, 94) and serum enzyme levels (85,87,92), but these loci have not been associated with histological features of NASH or cirrhosis. On the other hand, LEPR is only associated with ALT levels and histologically defined NASH (82,87), and HSD17B13 is associated with NASH and cirrhosis (80,84).…”

Section: Genetic Associations In the Context Of Nafld Phenotypic And Diagnostic Heterogeneitymentioning

confidence: 99%

“…These enzymatic indicators of inflammation and liver disease were associated with 517 SNPs, including variants in SERPINA1 , APOE, GPAM, MARC1 , and LEPR . The number of variants associated with any combination of ALT, ALP, and GGT is likely greater than the number found by studies that used imaging or histology to assess NAFLD because serum levels are not specific to NAFLD and are reflective of many processes in the body, including cardiovascular disease ( 87 ).…”

Section: Genetic Approaches For Nafld Therapeutic Target Identificationmentioning

confidence: 99%

“…Each ribbon represents a significant association identified between each gene and the described state. * indicates histologically defined state ( 56 , 80 , 82 , 84 – 87 , 89 – 96 ).…”

Section: Genetic Approaches For Nafld Therapeutic Target Identificationmentioning

confidence: 99%

“…Several other loci have been pleiotropically associated with multiple NAFLD stages. GCKR rs1260326 is associated with hepatic steatosis, as assessed by both imaging and histology ( 84 , 86 , 92 , 93 ), inflammation measured by serum enzyme levels ( 87 , 92 ), histological assessments of NAFLD graded by NAS ( 94 ), histological fibrosis ( 82 ), and overall liver function ( 88 ). MBOAT7 has similarly been examined across the entire spectrum of NAFLD, ranging from liver fat accumulation to cirrhosis ( 85 , 95 , 98 ), but intriguingly, it was found to be independently associated with fibrosis development in particular, suggesting a unique molecular mechanism ( 56 ).…”

Section: Genetic Approaches For Nafld Therapeutic Target Identificationmentioning

confidence: 99%

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Human Genetics to Identify Therapeutic Targets for NAFLD: Challenges and Opportunities

DeForest

Majithia

2021

Front. Endocrinol.

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Non-alcoholic fatty liver disease (NAFLD) is a continuous progression of pathophysiologic stages that is challenging to diagnose due to its inherent heterogeneity and poor standardization across a wide variety of diagnostic measures. NAFLD is heritable, and several loci have been robustly associated with various stages of disease. In the past few years, larger genetic association studies using new methodology have identified novel genes associated with NAFLD, some of which have shown therapeutic promise. This mini-review provides an overview of the heterogeneity in NAFLD phenotypes and diagnostic methods, discusses genetic associations in relation to the specific stages for which they were identified, and offers a perspective on the design of future genetic mapping studies to accelerate therapeutic target identification.

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Section: Genetic Associations Discovered In the Past Four Yearsmentioning

confidence: 93%

Section: Genetic Associations In the Context Of Nafld Phenotypic And Diagnostic Heterogeneitymentioning

confidence: 99%

Section: Genetic Approaches For Nafld Therapeutic Target Identificationmentioning

confidence: 99%

“…Each ribbon represents a significant association identified between each gene and the described state. * indicates histologically defined state ( 56 , 80 , 82 , 84 – 87 , 89 – 96 ).…”

Section: Genetic Approaches For Nafld Therapeutic Target Identificationmentioning

confidence: 99%

Section: Genetic Approaches For Nafld Therapeutic Target Identificationmentioning

confidence: 99%

See 3 more Smart Citations

Human Genetics to Identify Therapeutic Targets for NAFLD: Challenges and Opportunities

DeForest

Majithia

2021

Front. Endocrinol.

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Genome-Wide Investigation of Maximum Habitual Alcohol Intake in US Veterans in Relation to Alcohol Consumption Traits and Alcohol Use Disorder

et al. 2022

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ImportanceAlcohol genome-wide association studies (GWASs) have generally focused on alcohol consumption and alcohol use disorder (AUD); few have examined habitual drinking behaviors like maximum habitual alcohol intake (MaxAlc).ObjectivesTo identify genetic loci associated with MaxAlc and to elucidate the genetic architecture across alcohol traits.Design, Setting, and ParticipantsThis MaxAlc genetic association study was performed among Million Veteran Program participants enrolled from January 10, 2011, to September 30, 2020. Ancestry-specific GWASs were conducted in participants with European (n = 218 623) and African (n = 29 132) ancestry, then meta-analyzed (N = 247 755). Linkage-disequilibrium score regression was used to estimate single nucleotide variant (SNV)–heritability and genetic correlations (rg) with other alcohol and psychiatric traits. Genomic structural equation modeling (gSEM) was used to evaluate genetic associations between MaxAlc and other alcohol traits. Mendelian randomization was used to examine potential causal relationships between MaxAlc and liver enzyme levels. MTAG (multitrait analysis of GWAS) was used to analyze MaxAlc and problematic alcohol use (PAU) jointly.ExposuresGenetic associations.Main Outcomes and MeasuresMaxAlc was defined from the following survey item: “in a typical month, what is/was the largest number of drinks of alcohol you may have had in one day?” with ordinal responses from 0 to 15 or more drinks.ResultsGWASs were conducted on sample sizes of as many as 247 455 US veterans. Participants were 92.68% male and had mean (SD) age of 65.92 (11.70) years. The MaxAlc GWAS resulted in 15 genome-wide significant loci. Top associations in European-ancestry and African-ancestry participants were with known functional variants in the ADH1B gene, namely rs1229984 (P = 3.12 × 10−101) and rs2066702 (P = 6.30 × 10−17), respectively. Novel associations were also found. SNV-heritability was 6.65% (SE, 0.41) in European-ancestry participants and 3.42% (SE, 1.46) in African-ancestry participants. MaxAlc was positively correlated with PAU (rg = 0.79; P = 3.95 × 10−149) and AUD (rg = 0.76; P = 1.26 × 10−127) and had negative rg with the UK Biobank “alcohol usually taken with meals” (rg = −0.53; P = 1.40 × 10−50). For psychiatric traits, MaxAlc had the strongest genetic correlation with suicide attempt (rg = 0.40; P = 3.02 × 10−21). gSEM supported a 2-factor model with MaxAlc loading on a factor with PAU and AUD and other alcohol consumption measures loading on a separate factor. Mendelian randomization supported an association between MaxAlc and the liver enzyme gamma-glutamyltransferase (β = 0.012; P = 2.66 × 10−10). MaxAlc MTAG resulted in 31 genome-wide significant loci.Conclusions and RelevanceThe findings suggest that MaxAlc closely aligns genetically with PAU traits. This study improves understanding of the mechanisms associated with normative alcohol consumption vs problematic habitual use and AUD as well as how MaxAlc relates to psychiatric and medical conditions genetically and biologically.

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Persistently high serum aspartate aminotransferase level in an asymptomatic young patient

Pei,

Zhao,

Jiang

et al. 2023

Clinical Case Reports

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Key Clinical MessageWe report a young man with isolated elevated AST. He had no other evidence of liver or other related diseases. All the tests and examination reports were negative. The final diagnosis of macro‐AST was confirmed by PEG precipitation tests.AbstractElevated liver enzymes, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), may commonly indicate liver injury. However, macro‐AST is generally a benign condition that may be considered as pathologic by clinicians. A young man with isolated elevated AST for more than 10 years who have taken extensive tests and examinations was diagnosed with macro‐AST in our article. Thus, in patients with isolated AST‐elevation, polyethylene glycol (PEG) precipitation test was recommended to test whether macro‐AST could be diagnosed.

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Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes

Cited by 78 publications

References 53 publications

Human Genetics to Identify Therapeutic Targets for NAFLD: Challenges and Opportunities

Human Genetics to Identify Therapeutic Targets for NAFLD: Challenges and Opportunities

Genome-Wide Investigation of Maximum Habitual Alcohol Intake in US Veterans in Relation to Alcohol Consumption Traits and Alcohol Use Disorder

Persistently high serum aspartate aminotransferase level in an asymptomatic young patient

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