INSIG1 influences obesity-related hypertriglyceridemia in humans

In our analysis of a quantitative trait locus (QTL) for plasma triglyceride (TG) levels [logarithm of odds (LOD) = 3.7] on human chromosome 7q36, we examined 29 single nucleotide polymorphisms (SNPs) across INSIG1, a biological candidate gene in the region. Insulin-induced genes (INSIGs) are feedback mediators of cholesterol and fatty acid synthesis in animals, but their role in human lipid regulation is unclear. In our cohort, the INSIG1 promoter SNP rs2721 was associated with TG levels (P = 2 × 10−3 in 1,560 individuals of the original linkage cohort, P = 8 × 10−4 in 920 unrelated individuals of the replication cohort, combined P = 9.9 × 10−6). Individuals homozygous for the T allele had 9% higher TG levels and 2-fold lower expression of INSIG1 in surgical liver biopsy samples when compared with individuals homozygous for the G allele. Also, the T allele showed additional binding of nuclear proteins from HepG2 liver cells in gel shift assays. Finally, the variant rs7566605 in INSIG2, the only homolog of INSIG1, enhances the effect of rs2721 (P = 0.00117). The variant rs2721 alone explains 5.4% of the observed linkage in our cohort, suggesting that additional, yet-undiscovered genes and sequence variants in the QTL interval also contribute to alterations in TG levels in humans. In our analysis of a quantitative trait locus (QTL) for plasma triglyceride (TG) levels [logarithm of odds (LOD) = 3.7] on human chromosome 7q36, we examined 29 single nucleotide polymorphisms (SNPs) across INSIG1, a biological candidate gene in the region. Insulin-induced genes (INSIGs) are feedback mediators of cholesterol and fatty acid synthesis in animals, but their role in human lipid regulation is unclear. In our cohort, the INSIG1 promoter SNP rs2721 was associated with TG levels (P = 2 × 10−3 in 1,560 individuals of the original linkage cohort, P = 8 × 10−4 in 920 unrelated individuals of the replication cohort, combined P = 9.9 × 10−6). Individuals homozygous for the T allele had 9% higher TG levels and 2-fold lower expression of INSIG1 in surgical liver biopsy samples when compared with individuals homozygous for the G allele. Also, the T allele showed additional binding of nuclear proteins from HepG2 liver cells in gel shift assays. Finally, the variant rs7566605 in INSIG2, the only homolog of INSIG1, enhances the effect of rs2721 (P = 0.00117). The variant rs2721 alone explains 5.4% of the observed linkage in our cohort, suggesting that additional, yet-undiscovered genes and sequence variants in the QTL interval also contribute to alterations in TG levels in humans. Increased plasma triglyceride (TG) levels are an important cardiovascular risk factor and are strongly associated with atherosclerotic heart disease (1Forrester J.S. Triglycerides: risk factor or fellow traveler?.Curr. Opin. Cardiol. 2001; 16: 261-264Crossref PubMed Scopus (40) Google Scholar, 2Malloy M.J. Kane J.P. A risk factor for atherosclerosis: triglyceride-rich lipoproteins.Adv. Intern. Med. 2001; 47: 111-136PubMed Google Scholar). Plasma TG levels vary widely between individuals, and both genetic and environmental factors have been shown to contribute to elevated plasma TG concentrations (3Connelly P.W. Petrasovits A. Stachenko S. MacLean D.R. Little J.A. Chockalingam A. Prevalence of high plasma triglyceride combined with low HDL-C levels and its association with smoking, hypertension, obesity, diabetes, sedentariness and LDL-C levels in the Canadian population. Canadian Heart Health Surveys Research Group.Can. J. Cardiol. 1999; 15: 428-433PubMed Google Scholar, 4Tai E.S. Emmanuel S.C. Chew S.K. Tan B.Y. Tan C.E. Isolated low HDL cholesterol: an insulin-resistant state only in the presence of fasting hypertriglyceridemia.Diabetes. 1999; 48: 1088-1092Crossref PubMed Scopus (53) Google Scholar, 5Austin M.A. King M.C. Bawol R.D. Hulley S.B. Friedman G.D. Risk factors for coronary heart disease in adult female twins. Genetic heritability and shared environmental influences.Am. J. Epidemiol. 1987; 125: 308-318Crossref PubMed Scopus (184) Google Scholar, 6Heller D.A. de Faire U. Pedersen N.L. Dahlen G. McClearn G.E. Genetic and environmental influences on serum lipid levels in twins.N. Engl. J. Med. 1993; 328: 1150-1156Crossref PubMed Scopus (398) Google Scholar, 7Perusse L. Rice T. Despres J.P. Bergeron J. Province M.A. Gagnon J. Leon A.S. Rao D.C. Skinner J.S. Wilmore J.H. et al.Familial resemblance of plasma lipids, lipoproteins and postheparin lipoprotein and hepatic lipases in the HERITAGE Family Study.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 3263-3269Crossref PubMed Scopus (149) Google Scholar). Elevated plasma TG levels are often observed in obese and diabetic individuals and in individuals affected by the metabolic syndrome, a common chronic disorder associated with obesity, insulin resistance, hypertension, and alterations in plasma lipid profile such as elevated serum TG and low HDL levels. This characteristic pattern is similar to lipid abnormalities reported in familial combined hyperlipidemia (8Kissebah A.H. Alfarsi S. Adams P.W. Integrated regulation of very low density lipoprotein triglyceride and apolipoprotein-B kinetics in man: normolipemic subjects, familial hypertriglyceridemia and familial combined hyperlipidemia.Metabolism. 1981; 30: 856-868Abstract Full Text PDF PubMed Scopus (174) Google Scholar). The Metabolic Risk Complications of Obesity Genes (MRC-OB) project was established in 1994 to identify the genetic determinants of the metabolic syndrome and its metabolic abnormalities (9Kissebah A.H. Sonnenberg G.E. Myklebust J. Goldstein M. Broman K. James R.G. Marks J.A. Krakower G.R. Jacob H.J. Weber J. et al.Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome.Proc. Natl. Acad. Sci. USA. 2000; 97: 14478-14483Crossref PubMed Scopus (571) Google Scholar). As part of the project, basic anthropomorphic phenotypes, plasma lipid measures, and fasting glucose and insulin levels were ascertained for 2,209 individuals from 507 families. A genome-wide linkage scan of these families identified a quantitative trait locus (QTL) on human chromosome 7q36 linked to plasma TG levels (LOD = 3.7) (10Sonnenberg G.E. Krakower G.R. Martin L.J. Olivier M. Kwitek A.E. Comuzzie A.G. Blangero J. Kissebah A.H. Genetic determinants of obesity-related lipid traits.J. Lipid Res. 2004; 45: 610-615Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar). This region has also been implicated in numerous other studies (11Li W.D. Dong C. Li D. Garrigan C. Price R.A. A genome scan for serum triglyceride in obese nuclear families.J. Lipid Res. 2005; 46: 432-438Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 12Duggirala R. Blangero J. Almasy L. Dyer T.D. Williams K.L. Leach R.J. O’Connell P. Stern M.P. A major susceptibility locus influencing plasma triglyceride concentrations is located on chromosome 15q in Mexican Americans.Am. J. Hum. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, A. of linkage analysis for genome-wide of with to the in the Heart PubMed Google Scholar, J.P. scan on plasma triglyceride and high density lipoprotein cholesterol for the of quantitative PubMed Google Scholar, P.W. et for a gene influencing the on chromosome a genome-wide scan in the 2000; PubMed Scopus Google and of the for and elevated TG levels. The interval on chromosome 7q36 gene the only biological INSIG1 was as an K. K.L. R. and of a of Biol. 1993; Full Text PDF PubMed Google Scholar). was INSIG1 and to chromosome 7q36 M.A. A. R. human and and hepatic expression of the 1997; PubMed Scopus (53) Google Scholar). INSIG1 has been shown to the feedback regulation of cholesterol T. D. R. Goldstein in cholesterol binding of to a that of in Full Text Full Text PDF PubMed Scopus Google Scholar, A. H.J. Goldstein of from to by binding to Natl. Acad. Sci. USA. PubMed Scopus Google Scholar). binding proteins are factors located in the the synthesis of cholesterol and fatty cholesterol levels to proteins to to the Goldstein A that the cholesterol of and Natl. Acad. Sci. USA. 1999; PubMed Scopus Google Scholar). The to the to the of INSIG1 S. of in fatty acid and fatty Biol. Full Text Full Text PDF PubMed Scopus Google that are in the synthesis of cholesterol and fatty As levels to INSIG1, the of the to the T. D. R. Goldstein in cholesterol binding of to a that of in Full Text Full Text PDF PubMed Scopus Google and the synthesis of cholesterol and fatty Goldstein of the of cholesterol and fatty acid synthesis in the PubMed Scopus Google Scholar, R.A. for Full Text Full Text PDF PubMed Scopus Google INSIG1 and its only INSIG2, also their feedback of cholesterol synthesis by binding to and of the of a R.A. regulation of cholesterol and of Res. PubMed Scopus Google of INSIG1 has been shown to high levels of TG in both liver and plasma of diabetic fatty K. L. Li J. or in obese diabetic fatty and in Natl. Acad. Sci. USA. 2004; PubMed Scopus Google Scholar). has been that effect is to the T. D. R. Goldstein in cholesterol binding of to a that of in Full Text Full Text PDF PubMed Scopus Google Scholar). In single of INSIG1 or in to of both cholesterol and TG in an effect when both genes are L.J. G. K. Li Goldstein effect regulation of cholesterol synthesis in by 2005; PubMed Scopus Google Scholar). studies that INSIG1 and contribute to the and regulation of lipid in on we that sequence in INSIG1, is located in the QTL region on human chromosome 7q36 linked to plasma TG to the observed genetic effect on plasma lipid levels. we on our association analysis of sequence variants in INSIG1 in the and a replication of unrelated individuals, and for a effect of an associated sequence variant in INSIG1 with a variant in on plasma TG levels. our that a promoter variant in INSIG1 gene expression of INSIG1 in liver by the binding of nuclear factors to the promoter a on genetic to plasma TG levels. and have been in (9Kissebah A.H. Sonnenberg G.E. Myklebust J. Goldstein M. Broman K. James R.G. Marks J.A. Krakower G.R. Jacob H.J. Weber J. et al.Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome.Proc. Natl. Acad. Sci. USA. 2000; 97: 14478-14483Crossref PubMed Scopus (571) Google Scholar, G.E. Krakower G.R. Martin L.J. Olivier M. Kwitek A.E. Comuzzie A.G. Blangero J. Kissebah A.H. Genetic determinants of obesity-related lipid traits.J. Lipid Res. 2004; 45: 610-615Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar). In families with obese the of and or obese were from the in Health of was by a Individuals with the were from of or hepatic coronary or of of in the and individuals and and fasting plasma levels of and A of 2,209 individuals 507 families of for the and the of 1,560 individuals from families that to the linkage on chromosome 7q36 were for studies reported studies were from a of unrelated individuals of by the from the from 920 unrelated individuals were for were by the of the of and an on the in are in for the in the original 1,560 individuals of the and 920 unrelated individuals of the replication Family in a nucleotide polymorphisms (SNPs) were as for studies M. The for SNP Res. 2005; PubMed Scopus Google Scholar, M. D. K. de A. J. D. et of single nucleotide polymorphisms Res. 30: PubMed Scopus Google Scholar, Olivier M. J.A. D.R. influencing in and by 2001; PubMed Scopus Google Scholar, Olivier M. J.A. influence human plasma triglyceride PubMed Google Scholar). was in a of of of of of and were for and for were on an as M. D. K. de A. J. D. et of single nucleotide polymorphisms Res. 30: PubMed Scopus Google Scholar). The of in the analysis is shown in A region was in unrelated individuals from the The region was by in were and in for was with and on an SNP loci were identified by D.A. the and of single nucleotide Res. 1997; PubMed Scopus Google and were for were by with the chromosome sequence the in L. A to 1999; PubMed Scopus Google and to for and of the liver samples as as and were as M.P. Dyer T.D. J. L.J. Comuzzie A.G. et of expression in human PubMed Scopus Google Scholar). a liver biopsy was from of obese of was and of expression for liver samples were to et M.P. Dyer T.D. J. L.J. Comuzzie A.G. et of expression in human PubMed Scopus Google Scholar). identify with quantitative expression in the of expression for a were compared with of the in were identified an of the influence of and a biological between individuals, of were by individuals of by across by the and its as by et M.P. Dyer T.D. J. L.J. Comuzzie A.G. et of expression in human PubMed Scopus Google Scholar). the analysis of expression in INSIG1, individuals were to and their expression were compared for between were compared The human HepG2 was in with 2 of and and with both of the INSIG1 promoter SNP to the were and by shift was as J. J.A. in analysis of of the human to Biol. PubMed Scopus Google Scholar). nuclear were from 8 × were in and nuclear proteins were for on with of in a binding proteins were with for on and on and a of was of the with and with was on As TG levels are the were examined for from TG levels an of high the were were and were as In TG were for by by and 2 for association with in INSIG1, we identified in the INSIG1 gene region from the the in with J. M.J. analysis and of and 2005; PubMed Scopus Google Scholar, R. S.B. M.J. D. and in genetic association 2005; PubMed Scopus Google Scholar). the promoter and the of INSIG1 in unrelated individuals, we identified an additional 17 were in the = and were for association with we the to for in the of the SNP by such that the of and and the an D. to quantitative and Scholar). for the between we analysis with the as in the L. Blangero J. linkage analysis in J. Hum. Full Text Full Text PDF PubMed Scopus Google Scholar). identified in the we SNP rs2721 in a of 920 unrelated were as and were the TG were to of the As was an unrelated cohort, we analysis the combined effect of rs2721 in both we combined the the This is by et M.C. from the is to Biol. 2005; PubMed Scopus Google and in the was an between INSIG1 and INSIG2, as from we examined the between the for TG the loci M. P. A. on chromosome 2 and to susceptibility to in Mexican 1999; PubMed Scopus Google Scholar). we in and that had been reported to associated with and LDL-C in other studies A. A. T. T. D. et common genetic variant is associated with adult and PubMed Scopus Google Scholar, K. M. T. S. K. R. J. et gene rs7566605 is associated with in Hum. PubMed Scopus Google Scholar, K. K. T. T. The single nucleotide of gene 2 is associated with the of but with obesity, in J. PubMed Scopus Google and for both and the analysis in we examined the of INSIG1 variants on were by the by and analysis for the effect of INSIG1 The QTL on chromosome linked to plasma TG levels has been in (10Sonnenberg G.E. Krakower G.R. Martin L.J. Olivier M. Kwitek A.E. Comuzzie A.G. Blangero J. Kissebah A.H. Genetic determinants of obesity-related lipid traits.J. Lipid Res. 2004; 45: 610-615Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, W.D. Dong C. Li D. Garrigan C. Price R.A. A genome scan for serum triglyceride in obese nuclear families.J. Lipid Res. 2005; 46: 432-438Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 12Duggirala R. Blangero J. Almasy L. Dyer T.D. Williams K.L. Leach R.J. O’Connell P. Stern M.P. A major susceptibility locus influencing plasma triglyceride concentrations is located on chromosome 15q in Mexican Americans.Am. J. Hum. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, A. of linkage analysis for genome-wide of with to the in the Heart PubMed Google Scholar, J.P. scan on plasma triglyceride and high density lipoprotein cholesterol for the of quantitative PubMed Google Scholar, P.W. et for a gene influencing the on chromosome a genome-wide scan in the 2000; PubMed Scopus Google Scholar). the identified genes in INSIG1 is the only candidate with biological that are to lipid and has been the of we for INSIG1 association from the the of J. M.J. analysis and of and 2005; PubMed Scopus Google Scholar, R. S.B. M.J. D. and in genetic association 2005; PubMed Scopus Google and the INSIG1 gene region variant in the promoter region of INSIG1, was associated with plasma TG levels in 1,560 individuals from our (P = additional and located in of INSIG1 showed association (P = and P = as as additional SNP in the promoter region P = As these associated are in linkage with rs2721 we that their high of have to the observed of SNP association in a The promoter variant is located of the of other variants rs2721 in the association we the promoter region and in unrelated individuals from our in the of the gene were in high linkage with other and in with we on the region individuals were from families to the observed linkage on in the The 17 additional of 8 were and reported in The of is shown in were in the 1,560 individuals from the The of the association analysis are in additional were associated with plasma TG levels in cohort, suggesting that the effect is by The TG levels of individuals homozygous for the G allele = were on 9% lower of individuals homozygous for the T allele = we examined the effect of the SNP on the the QTL interval on chromosome 7q36 explains of the in TG levels in our SNP rs2721 in INSIG1 as a the linkage 5.4% for our cohort, suggesting a but effect on the linkage on chromosome 7q36 that explains of the observed in TG levels in the the association in the cohort, we examined the effect of the associated variant rs2721 in a The of the are in A of 920 individuals were and in the The allele of rs2721 in is to the of rs2721 in the rs2721 was strongly associated with plasma TG levels (P = 8 × the in our In replication cohort, individuals homozygous for the T allele of rs2721 = had TG levels of compared with for individuals homozygous for the G allele = both are combined a M.C. from the is to Biol. 2005; PubMed Scopus Google rs2721 is associated with TG levels with a of 9.9 × rs2721 have a we examined the sequence variant is with INSIG1 expression the SNP is located in the promoter region of the examined expression levels of INSIG1 in liver biopsy samples from obese individuals were for and gene expression levels were compared The T allele INSIG1 gene expression levels In individuals with = had 2-fold lower levels of INSIG1 compared with with TG = P = or = P = of P = INSIG1 expression in individuals was from homozygous individuals (P = on observed between INSIG1 gene expression and rs2721 we the have to nuclear proteins such as the levels that to the lipid SNP rs2721 both and As shown in the presence of the T allele in the promoter to a shift in observed binding of nuclear from HepG2 cells compared with the G allele. This shift is in nuclear or that the of rs2721 have to nuclear the binding to the sequence rs2721 are is that binding the observed in INSIG1 gene expression and plasma TG levels in individuals homozygous for the T allele. In the INSIG1 is similar to its only INSIG1 is in the feedback regulation of lipid has been shown to associated with and in a of studies A. A. T. T. D. et common genetic variant is associated with adult and PubMed Scopus Google Scholar, K. M. T. S. K. R. J. et gene rs7566605 is associated with in Hum. PubMed Scopus Google Scholar, K. K. T. T. The single nucleotide of gene 2 is associated with the of but with obesity, in J. PubMed Scopus Google Scholar). to has these genes in to lipid as has been shown in L.J. G. K. Li Goldstein effect regulation of cholesterol synthesis in by 2005; PubMed Scopus Google Scholar). analysis on of the locus of INSIG1 and the locus of a between the genes = P on these we in and that have been shown to associated with and LDL-C in other studies A. A. T. T. D. et common genetic variant is associated with adult and PubMed Scopus Google Scholar, K. M. T. S. K. R. J. et gene rs7566605 is associated with in Hum. PubMed Scopus Google Scholar, K. K. T. T. The single nucleotide of gene 2 is associated with the of but with obesity, in J. PubMed Scopus Google Scholar). analysis was on the and rs2721 of In SNP effect on TG levels or with In SNP rs7566605 showed with rs2721 (P = was associated with TG levels. the of rs7566605 on the association of rs2721 with lipid we the on analysis was in these In the the with TG levels In in the the association was = P = 0.00117). individuals homozygous for the T allele of rs2721 had higher TG levels individuals homozygous for the G allele we the on of the between the INSIG1 rs2721 homozygous was only analysis of rs7566605 in and rs2721 in The of rs7566605 enhances the association of rs2721 with plasma TG and = = = when compared with of rs2721 (P = 0.00117). in a = when compared with of rs2721 (P = 0.00117). in have and of genes in lipid L.J. G. K. Li Goldstein effect regulation of cholesterol synthesis in by 2005; PubMed Scopus Google Scholar). a that is to the to the of a of proteins have been as of both cholesterol and fatty acid synthesis T. D. R. Goldstein in cholesterol binding of to a that of in Full Text Full Text PDF PubMed Scopus Google Scholar, A. H.J. Goldstein of from to by binding to Natl. Acad. Sci. USA. PubMed Scopus Google Scholar, S. of in fatty acid and fatty Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). has shown of their in lipid in humans. on the that the gene for INSIG1 is located in a QTL region linked to plasma TG levels in our cohort, we examined the role of sequence variants in the gene in the of plasma TG levels. association analysis associated with TG levels. analysis of additional sequence variants by the promoter SNP rs2721 as the variant for the observed effect showed that homozygous for the T allele rs2721 had elevated plasma TG levels. The association was in a cohort, a similar effect in individuals homozygous for the T allele. that rs2721 in INSIG1 associated with TG levels in our linkage region. our analysis also that variant for only a of the linkage suggesting that other variants and genes in the QTL interval also plasma TG levels. rs2721 explains of the observed in TG levels in our This of the with other genes and locus have been in The SNP rs2721 of the of INSIG1 in the promoter region. the effect on the of INSIG1 in expression was in liver the for INSIG1 on lipid in analysis that individuals homozygous for the T allele had lower INSIG1 expression suggesting that expression of INSIG1 plasma TG levels. the expression analysis only individuals homozygous for the T allele in our of individuals, the for an effect of promoter variant on gene in samples and to to effect of effect of SNP rs2721 on the promoter of INSIG1, we examined the binding of nuclear proteins to the sequence rs2721 by for the of rs2721 and the sequence the SNP were for the T allele were to nuclear proteins from HepG2 in to the G allele that the T allele of rs2721 binding of nuclear proteins in the that sequence variant promoter of of the sequence that rs2721 is located in a binding for the factor is in the liver and a of other The binding is in the G the of binding the T allele. factors with binding to the of rs2721 factor and A. This binding the observed and to the observed expression of the factors have been reported to plasma TG levels. has been reported to glucose and and has been that in susceptibility to S.K. L. J.S. and in 30: PubMed Scopus Google Scholar). the proteins effect to the T expression of INSIG1, and plasma TG to the in with the expression analysis of the liver biopsy a for is that and additional studies to the has been shown in that for INSIG1 and its only homolog have lipid abnormalities compared with for gene L.J. G. K. Li Goldstein effect regulation of cholesterol synthesis in by 2005; PubMed Scopus Google Scholar). the effect of sequence variants in both human INSIG1 and on plasma on the SNP rs2721 of INSIG1, we the with variants that have shown to associated with and lipid abnormalities in on our INSIG1 with in to lipid The have effect on plasma TG levels in our rs7566605 enhances the effect with rs2721 of INSIG1, and their the association with plasma TG levels the rs7566605 of showed a effect of the of rs2721 in INSIG1 on TG levels. In individuals with allele rs7566605 of showed an effect of the T allele of rs2721 on that the G allele of to for the effect of rs2721 in the to our analysis that rs2721 plasma TG levels by INSIG1 gene expression in the This effect or by the of rs7566605 in a of in plasma TG of the of on LDL-C in a in risk of coronary heart disease in a by et M. J. of triglyceride levels lipoprotein cholesterol coronary syndrome in the Cardiol. PubMed Scopus Google Scholar). In our the in TG levels in individuals with the of rs2721 was and for families and unrelated individuals, when the was by of This effect is by the of the allele of rs7566605 in and the allele of in a in TG levels. the replication of the linkage on chromosome 7q36, genome-wide association studies to lipid have to association in INSIG1 other gene in the QTL region has been implicated in of the lipid the low linkage between rs2721 and of the on common is the association of rs2721 with plasma TG levels in our analysis was by the of association for the linkage to This effect has been reported and is to QTL region or lipid G.D. of genome-wide for Hum. PubMed Scopus Google Scholar). The of in other studies also to in the of the In our we individuals with hepatic coronary in the or individuals the of the these associated with and have a influence on the to the expression from liver samples from the levels of INSIG1 expression in the population. is the only gene and rs2721 the only sequence variant for the observed linkage on human chromosome 7q36, our for the a role for gene in the and regulation of plasma TG levels and a by the variant rs2721 its to the other genetic factors plasma TG levels in our and the effect on important cardiovascular disease risk factor in other shift genome-wide association studies genes linkage of odds allele Metabolic Risk Complications of Obesity Genes project quantitative trait locus proteins single nucleotide binding

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.