Whole-exome sequencing identifies rare genetic variants associated with human plasma metabolites

Bomba, Lorenzo; Walter, Klaudia; Guo, Qi; Surendran, Praveen; Kundu, Kousik; Nongmaithem, Suraj S.; Karim, Mohd Anisul; Stewart, Isobel D.; Langenberg, Claudia; Danesh, John; Angelantonio, Emanuele Di; Roberts, David; Ouwehand, Willem H.; Dunham, Ian; Butterworth, Adam S.; Soranzo, Nicole

doi:10.1016/j.ajhg.2022.04.009

Cited by 28 publications

(25 citation statements)

References 49 publications

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“…Overall, 245 (9.4%) associations were with rare variants, which accounted for 152 (9.9%) of conditionally independent variants. We used whole exome sequence (WES) data from a subset of INTERVAL participants 9 for technical validation of rare variant associations and found a strong correlation of effect sizes (R 2 = 0.98; Extended Data Fig. 2), confirming that the associations were not genotyping or imputation artefacts.…”

Section: Articlementioning

confidence: 84%

“…To ensure that rare variant associations were not due to technical artefacts of the imputation, we performed a technical validation using WES data in a subset of 3,924 samples from the INTERVAL study 9 . We looked up associations from analysis of the INTERVAL WES data for 122 (49.8%) of the total 245 rare variant associations for which variants and metabolites overlapped.…”

Section: Technical Validation Of Rare Variant Associationsmentioning

confidence: 99%

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Rare and common genetic determinants of metabolic individuality and their effects on human health

Surendran

Stewart

Yeung

et al. 2022

Nat Med

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Garrod’s concept of ‘chemical individuality’ has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals and identified 2,599 variant–metabolite associations (P < 1.25 × 10−11) within 330 genomic regions, with rare variants (minor allele frequency ≤ 1%) explaining 9.4% of associations. Jointly modeling metabolites in each region, we identified 423 regional, co-regulated, variant–metabolite clusters called genetically influenced metabotypes. We assigned causal genes for 62.4% of these genetically influenced metabotypes, providing new insights into fundamental metabolite physiology and clinical relevance, including metabolite-guided discovery of potential adverse drug effects (DPYD and SRD5A2). We show strong enrichment of inborn errors of metabolism-causing genes, with examples of metabolite associations and clinical phenotypes of non-pathogenic variant carriers matching characteristics of the inborn errors of metabolism. Systematic, phenotypic follow-up of metabolite-specific genetic scores revealed multiple potential etiological relationships.

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Section: Articlementioning

confidence: 84%

Section: Technical Validation Of Rare Variant Associationsmentioning

confidence: 99%

Rare and common genetic determinants of metabolic individuality and their effects on human health

Surendran

Stewart

Yeung

et al. 2022

Nat Med

Self Cite

View full text Add to dashboard Cite

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“…The reference genome for aligning WES was human GRCh37/hg19. SNPs and indels were called by SAMtools, correcting for overestimated mapping quality from Burrows-Wheeler Alignment tool ( 14 ).…”

Section: Methodsmentioning

confidence: 99%

Precision therapy for three Chinese families with maturity-onset diabetes of the young (MODY12)

Wang

Mao

et al. 2022

Front. Endocrinol.

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Maturity-onset diabetes of the young (MODY) is rare monogenic diabetes. However, MODY is often undiagnosed or misdiagnosed. In this study, we aimed to investigate the pathogenic gene for diabetes and provide precise treatment for diabetes patients in three families. Three families with suspected MODY were enrolled and screened for germline mutations using Whole exome sequencing (WES). Candidate pathogenic variants were validated in other family members and non-related healthy controls. Three heterozygous missense mutations in the ABCC8 gene (NM_001287174), c.1555 C>T (p.R519C), c.3706 A>G (p.I1236V), and c.2885 C>T (p.S962L) were found in families A, B, and C, respectively. All mutation sites cosegregated with diabetes, were predicted to be harmful by bioinformatics and were not found in non-related healthy controls. Two probands (onset ages, 8 and 12 years) were sensitive to glimepiride. However, an insufficient dose (2 mg/day) led to ketoacidosis. When the dosage of glimepiride was increased to 4 mg/day, blood sugar remained under control. A dose of 4 mg glimepiride daily also effectively controlled blood sugar in an adult patient 25-year-old. In addition, all patients were sensitive to liraglutide, which could control blood sugar better. These data suggest that ABCC8 was the pathogenic gene in three families with diabetes. Glimepiride (2 mg/day) was not effective in controlling blood sugar in children with ABCC8 mutations, however, 4 mg/daily glimepiride was effective in both adults and children. Moreover, liraglutide was effective in controlling blood sugar in both adults and children with ABCC8 mutations.

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“…While many studies have focused on the genetic determinants of blood metabolites [10][11][12][13][14][15] , research focusing specifically on bile acids in a large sample from the general population is currently lacking. Here we investigate the genetic architecture of primary and secondary BAs, reporting associations with both common and low-frequency/rare variants.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide association study reveals loci with sex-specific effects on plasma bile acids

Landini

Ghasemi-Semeskandeh

Johansson

et al. 2022

Preprint

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Bile acids are essential for food digestion and nutrient absorption, but also act as signalling molecules involved in hepatobiliary diseases, gastrointestinal disorders and carcinogenesis. While many studies have focused on the genetic determinants of blood metabolites, research focusing specifically on genetic regulation of bile acids in the general population is currently lacking. Here we investigate the genetic architecture of primary and secondary bile acids in blood plasma, reporting associations with both common and rare variants. By performing genome-wide association analysis (GWAS) of plasma blood levels of 18 bile acids (N = 4923) we identify two significantly associated loci, a common variant mapping to SLCO1B1 (encoding a liver bilirubin and drug transporter) and a rare variant in PRKG1 (encoding soluble cyclic GMP-dependent protein kinase). For these loci, in the sex-stratified GWAS (N♂ = 820, N♀ = 1088), we observe sex-specific effects (SLCO1B1 β ♂ = -0.51, P = 2.30x10-13, β♀ = -0.3, P = 9.90x10-07; PRKG1 β ♂ = -0.18, P = 1.80x10-01, β ♀ = -0.79, P = 8.30x10-11), corroborating the contribution of sex to bile acid variability. Using gene-based aggregate tests and whole exome sequencing, we identify rare pLoF and missense variants potentially associated with bile acid levels in 3 genes (OR1G1, SART1 and SORCS2), some of which have been linked with liver diseases.

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Whole-exome sequencing identifies rare genetic variants associated with human plasma metabolites

Cited by 28 publications

References 49 publications

Rare and common genetic determinants of metabolic individuality and their effects on human health

Rare and common genetic determinants of metabolic individuality and their effects on human health

Precision therapy for three Chinese families with maturity-onset diabetes of the young (MODY12)

Genome-wide association study reveals loci with sex-specific effects on plasma bile acids

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