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Population-specific coding variant underlies genome-wide association with adiponectin level.

ABSTRACT: Adiponectin is a protein hormone that can affect major metabolic processes including glucose regulation and fat metabolism. Our previous genome-wide association (GWA) study of circulating plasma adiponectin levels in Filipino women from the Cebu Longitudinal Health and Nutrition Survey (CLHNS) detected a 100 kb two-SNP haplotype at KNG1-ADIPOQ associated with reduced adiponectin (frequency = 0.050, P = 1.8 × 10(-25)). Subsequent genotyping of CLHNS young adult offspring detected an uncommon variant [minor allele frequency (MAF) = 0.025] located ~800 kb from ADIPOQ that showed strong association with lower adiponectin levels (P = 2.7 × 10(-15), n = 1695) and tagged a subset of KNG1-ADIPOQ haplotype carriers with even lower adiponectin levels. Sequencing of the ADIPOQ-coding region detected variant R221S (MAF = 0.015, P = 2.9 × 10(-69)), which explained 17.1% of the variance in adiponectin levels and largely accounted for the initial GWA signal in Filipinos. R221S was not present in 12 514 Europeans with previously sequenced exons. To explore the mechanism of this substitution, we re-measured adiponectin level in 20 R221S offspring carriers and 20 non-carriers using two alternative antibodies and determined that the presence of R221S resulted in artificially low quantification of adiponectin level using the original immunoassay. These data provide an example of an uncommon variant responsible for a GWA signal and demonstrate that genetic associations with phenotypes measured by antibody-based quantification methods can be affected by uncommon coding SNPs residing in the antibody target region.

SUBMITTER: Croteau-Chonka DC

PROVIDER: S-EPMC3276282 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Population-specific coding variant underlies genome-wide association with adiponectin level.

Croteau-Chonka Damien C DC Wu Ying Y Li Yun Y Fogarty Marie P MP Lange Leslie A LA Kuzawa Christopher W CW McDade Thomas W TW Borja Judith B JB Luo Jingchun J AbdelBaky Omar O Combs Terry P TP Adair Linda S LS Lange Ethan M EM Mohlke Karen L KL

Human molecular genetics 20111018 2

Adiponectin is a protein hormone that can affect major metabolic processes including glucose regulation and fat metabolism. Our previous genome-wide association (GWA) study of circulating plasma adiponectin levels in Filipino women from the Cebu Longitudinal Health and Nutrition Survey (CLHNS) detected a 100 kb two-SNP haplotype at KNG1-ADIPOQ associated with reduced adiponectin (frequency = 0.050, P = 1.8 × 10(-25)). Subsequent genotyping of CLHNS young adult offspring detected an uncommon vari ...[more]

PMID: 22010046

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Project description:ImportanceWith the current opioid crisis, it is important to improve understanding of the biological mechanisms of opioid use disorder (OUD).ObjectivesTo detect genetic risk variants for OUD and determine genetic correlations and causal association with OUD and other traits.Design, setting, and participantsA genome-wide association study of electronic health record-defined OUD in the Million Veteran Program sample was conducted, comprising 8529 affected European American individuals and 71 200 opioid-exposed European American controls (defined by electronic health record trajectory analysis) and 4032 affected African American individuals and 26 029 opioid-exposed African American controls. Participants were enrolled from January 10, 2011, to May 21, 2018, with electronic health record data for OUD diagnosis from October 1, 1999, to February 7, 2018. Million Veteran Program results and additional OUD case-control genome-wide association study results from the Yale-Penn and Study of Addiction: Genetics and Environment samples were meta-analyzed (total numbers: European American individuals, 10 544 OUD cases and 72 163 opioid-exposed controls; African American individuals, 5212 cases and 26 876 controls). Data on Yale-Penn participants were collected from February 14, 1999, to April 1, 2017, and data on Study of Addiction: Genetics and Environment participants were collected from 1990 to 2007. The key result was replicated in 2 independent cohorts: proxy-phenotype buprenorphine treatment in the UK Biobank and newly genotyped Yale-Penn participants. Genetic correlations between OUD and other traits were tested, and mendelian randomization analysis was conducted to identify potential causal associations.Main outcomes and measuresMain outcomes were International Classification of Diseases, Ninth Revision-diagnosed OUD or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision-diagnosed OUD (Million Veteran Program), and DSM-IV-defined opioid dependence (Yale-Penn and Study of Addiction: Genetics and Environment).ResultsA total of 114 759 individuals (101 016 men [88%]; mean [SD] age, 60.1 [12.8] years) were included. In 82 707 European American individuals, a functional coding variant (rs1799971, encoding Asn40Asp) in OPRM1 (μ-opioid receptor gene, the main biological target for opioid drugs; OMIM 600018) reached genome-wide significance (G allele: β = -0.066 [SE = 0.012]; P = 1.51 × 10-8). The finding was replicated in 2 independent samples. Single-nucleotide polymorphism-based heritability of OUD was 11.3% (SE = 1.8%). Opioid use disorder was genetically correlated with 83 traits, including multiple substance use traits, psychiatric illnesses, cognitive performance, and others. Mendelian randomization analysis revealed the following associations with OUD: risk of tobacco smoking, depression, neuroticism, worry neuroticism subcluster, and cognitive performance. No genome-wide significant association was detected for African American individuals or in transpopulation meta-analysis.Conclusions and relevanceThis genome-wide meta-analysis identified a significant association of OUD with an OPRM1 variant, which was replicated in 2 independent samples. Post-genome-wide association study analysis revealed associated pleiotropic characteristics. Recruitment of additional individuals with OUD for future studies-especially those of non-European ancestry-is a crucial next step in identifying additional significant risk loci.

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Population-specific coding variant underlies genome-wide association with adiponectin level.

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Population-specific coding variant underlies genome-wide association with adiponectin level.

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