Xiangjun Gu

Genetic loci associated with plasma phospholipid N-3 fatty acids: A Meta-Analysis of Genome-Wide association studies from the charge consortium

Long-chain n-3 polyunsaturated fatty acids (PUFAs) can derive from diet or from α-linolenic acid (ALA) by elongation and desaturation. We investigated the association of common genetic variation with plasma phospholipid levels of the four major n-3 PUFAs by performing genome-wide association studies in five population-based cohorts comprising 8,866 subjects of European ancestry. Minor alleles of SNPs in FADS1 and FADS2 (desaturases) were associated with higher levels of ALA (pu200a=u200a3×10−64) and lower levels of eicosapentaenoic acid (EPA, pu200a=u200a5×10−58) and docosapentaenoic acid (DPA, pu200a=u200a4×10−154). Minor alleles of SNPs in ELOVL2 (elongase) were associated with higher EPA (pu200a=u200a2×10−12) and DPA (pu200a=u200a1×10−43) and lower docosahexaenoic acid (DHA, pu200a=u200a1×10−15). In addition to genes in the n-3 pathway, we identified a novel association of DPA with several SNPs in GCKR (glucokinase regulator, pu200a=u200a1×10−8). We observed a weaker association between ALA and EPA among carriers of the minor allele of a representative SNP in FADS2 (rs1535), suggesting a lower rate of ALA-to-EPA conversion in these subjects. In samples of African, Chinese, and Hispanic ancestry, associations of n-3 PUFAs were similar with a representative SNP in FADS1 but less consistent with a representative SNP in ELOVL2. Our findings show that common variation in n-3 metabolic pathway genes and in GCKR influences plasma phospholipid levels of n-3 PUFAs in populations of European ancestry and, for FADS1, in other ancestries.

Effects of long-term averaging of quantitative blood pressure traits on the detection of genetic associations

Blood pressure (BP) is a heritable, quantitative trait with intraindividual variability and susceptibility to measurement error. Genetic studies of BP generally use single-visit measurements and thus cannot remove variability occurring over months or years. We leveraged the idea that averaging BP measured across time would improve phenotypic accuracy and thereby increase statistical power to detect genetic associations. We studied systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP) averaged over multiple years in 46,629 individuals of European ancestry. We identified 39 trait-variant associations across 19 independent loci (p < 5 × 10(-8)); five associations (in four loci) uniquely identified by our LTA analyses included those of SBP and MAP at 2p23 (rs1275988, near KCNK3), DBP at 2q11.2 (rs7599598, in FER1L5), and PP at 6p21 (rs10948071, near CRIP3) and 7p13 (rs2949837, near IGFBP3). Replication analyses conducted in cohorts with single-visit BP data showed positive replication of associations and a nominal association (p < 0.05). We estimated a 20% gain in statistical power with long-term average (LTA) as compared to single-visit BP association studies. Using LTA analysis, we identified genetic loci influencing BP. LTA might be one way of increasing the power of genetic associations for continuous traits in extant samples for other phenotypes that are measured serially over time.

Genome-Wide association study of plasma n6 polyunsaturated fatty acids within the cohorts for heart and aging research in genomic epidemiology consortium

Background—Omega6 (n6) polyunsaturated fatty acids (PUFAs) and their metabolites are involved in cell signaling, inflammation, clot formation, and other crucial biological processes. Genetic components, such as variants of fatty acid desaturase (FADS) genes, determine the composition of n6 PUFAs. Methods and Results—To elucidate undiscovered biological pathways that may influence n6 PUFA composition, we conducted genome-wide association studies and meta-analyses of associations of common genetic variants with 6 plasma n6 PUFAs in 8631 white adults (55% women) across 5 prospective studies. Plasma phospholipid or total plasma fatty acids were analyzed by similar gas chromatography techniques. The n6 fatty acids linoleic acid (LA), &ggr;-linolenic acid (GLA), dihomo-GLA, arachidonic acid, and adrenic acid were expressed as percentage of total fatty acids. We performed linear regression with robust SEs to test for single-nucleotide polymorphism–fatty acid associations, with pooling using inverse-variance–weighted meta-analysis. Novel regions were identified on chromosome 10 associated with LA (rs10740118; P=8.1×10−9; near NRBF2), on chromosome 16 with LA, GLA, dihomo-GLA, and arachidonic acid (rs16966952; P=1.2×10−15, 5.0×10−11, 7.6×10−65, and 2.4×10−10, respectively; NTAN1), and on chromosome 6 with adrenic acid after adjustment for arachidonic acid (rs3134950; P=2.1×10−10; AGPAT1). We confirmed previous findings of the FADS cluster on chromosome 11 with LA and arachidonic acid, and further observed novel genome-wide significant association of this cluster with GLA, dihomo-GLA, and adrenic acid (P=2.3×10−72, 2.6×10−151, and 6.3×10−140, respectively). Conclusions—Our findings suggest that along with the FADS gene cluster, additional genes may influence n6 PUFA composition.Background —Omega-6 (n6) polyunsaturated fatty acids (PUFAs) and their metabolites are involved in cell signaling, inflammation, clot formation, and other crucial biological processes. Genetic components, such as variants of fatty acid desaturase ( FADS ) genes, determine the composition of n6 PUFAs. nnMethods and Results —To elucidate undiscovered biologic pathways that may influence n6 PUFA composition, we conducted genome-wide association studies and meta-analyses of associations of common genetic variants with five plasma n6 PUFAs in 8,631 Caucasian adults (55% female) across five prospective studies. Plasma phospholipid or total plasma fatty acids were analyzed by similar gas chromatography techniques. The n6 fatty acids linoleic acid (LA), gamma-linolenic acid (GLA), dihomo-gamma-linoleic acid (DGLA), arachidonic acid (AA), and adrenic acid (AdrA) were expressed as % of total fatty acids. We performed linear regression with robust standard errors to test for SNP-fatty acid associations, with pooling using inverse-variance weighted meta-analysis. Novel regions were identified on chromosome 10 associated with LA (rs10740118, p-value = 8.1x10-9; near NRBF2 ); on chromosome 16 with LA, GLA, DGLA, and AA (rs16966952, p-value = 1.2x10-15, 5.0x10-11, 7.6x10-65, and 2.4x10-10, respectively; NTAN1 ); and on chromosome 6 with AdrA following adjustment for AA (rs3134950, p-value = 2.1x10-10; AGPAT1 ). We confirmed previous findings of the FADS cluster on chromosome 11 with LA and AA, and further observed novel genome-wide significant association of this cluster with GLA, DGLA, and AdrA (p-value = 2.3x10-72, 2.6x10-151, and 6.3x10-140, respectively). nnConclusions —Our findings suggest that along with the FADS gene cluster, additional genes may influence n6 PUFA composition.

Genome-wide association study identifies novel loci associated with concentrations of four plasma phospholipid fatty acids in the de novo lipogenesis pathway: Results from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium

Background— Palmitic acid (16:0), stearic acid (18:0), palmitoleic acid (16:1n-7), and oleic acid (18:1n-9) are major saturated and monounsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis and are the main saturated and monounsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes mellitus and coronary heart disease.nnMethods and Results— Genome-wide association studies were conducted in 5 population-based cohorts comprising 8961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these 4 fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of ≥1 of these fatty acids. ALG14 (asparagine-linked glycosylation 14 homolog) polymorphisms were associated with higher 16:0 ( P =2.7×10−11) and lower 18:0 ( P =2.2×10−18). FADS1 and FADS2 (desaturases) polymorphisms were associated with higher 16:1n-7 ( P =6.6×10−13) and 18:1n-9 ( P =2.2×10−32) and lower 18:0 ( P =1.3×10−20). LPGAT1 (lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0 ( P =2.8×10−9). GCKR (glucokinase regulator; P =9.8×10−10) and HIF1AN (factor inhibiting hypoxia-inducible factor-1; P =5.7×10−9) polymorphisms were associated with higher 16:1n-7, whereas PKD2L1 (polycystic kidney disease 2-like 1; P =5.7×10−15) and a locus on chromosome 2 (not near known genes) were associated with lower 16:1n-7 ( P =4.1×10−8).nnConclusions— Our findings provide novel evidence that common variations in genes with diverse functions, including protein-glycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of 4 fatty acids in the de novo lipogenesis pathway. These results expand our knowledge of genetic factors relevant to de novo lipogenesis and fatty acid biology.Background—Palmitic acid (16:0), stearic acid (18:0), palmitoleic acid (16:1n-7), and oleic acid (18:1n-9) are major saturated and monounsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis and are the main saturated and monounsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes mellitus and coronary heart disease. Methods and Results—Genome-wide association studies were conducted in 5 population-based cohorts comprising 8961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these 4 fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of ≥1 of these fatty acids. ALG14 (asparagine-linked glycosylation 14 homolog) polymorphisms were associated with higher 16:0 (P=2.7×10−11) and lower 18:0 (P=2.2×10−18). FADS1 and FADS2 (desaturases) polymorphisms were associated with higher 16:1n-7 (P=6.6×10−13) and 18:1n-9 (P=2.2×10−32) and lower 18:0 (P=1.3×10−20). LPGAT1 (lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0 (P=2.8×10−9). GCKR (glucokinase regulator; P=9.8×10−10) and HIF1AN (factor inhibiting hypoxia-inducible factor-1; P=5.7×10−9) polymorphisms were associated with higher 16:1n-7, whereas PKD2L1 (polycystic kidney disease 2-like 1; P=5.7×10−15) and a locus on chromosome 2 (not near known genes) were associated with lower 16:1n-7 (P=4.1×10−8). Conclusions—Our findings provide novel evidence that common variations in genes with diverse functions, including protein-glycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of 4 fatty acids in the de novo lipogenesis pathway. These results expand our knowledge of genetic factors relevant to de novo lipogenesis and fatty acid biology.

Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function

Background Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. Methods We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. Results The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P u200a=u200a 5.71 × 10-7). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P u200a=u200a 2.18 × 10-8) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. Conclusions In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.

Genome-Wide Association Study Identifies Novel Loci Associated With Concentrations of Four Plasma Phospholipid Fatty Acids in the De Novo Lipogenesis Pathway: Results from the CHARGE Consortium

Background— Palmitic acid (16:0), stearic acid (18:0), palmitoleic acid (16:1n-7), and oleic acid (18:1n-9) are major saturated and monounsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis and are the main saturated and monounsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes mellitus and coronary heart disease.nnMethods and Results— Genome-wide association studies were conducted in 5 population-based cohorts comprising 8961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these 4 fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of ≥1 of these fatty acids. ALG14 (asparagine-linked glycosylation 14 homolog) polymorphisms were associated with higher 16:0 ( P =2.7×10−11) and lower 18:0 ( P =2.2×10−18). FADS1 and FADS2 (desaturases) polymorphisms were associated with higher 16:1n-7 ( P =6.6×10−13) and 18:1n-9 ( P =2.2×10−32) and lower 18:0 ( P =1.3×10−20). LPGAT1 (lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0 ( P =2.8×10−9). GCKR (glucokinase regulator; P =9.8×10−10) and HIF1AN (factor inhibiting hypoxia-inducible factor-1; P =5.7×10−9) polymorphisms were associated with higher 16:1n-7, whereas PKD2L1 (polycystic kidney disease 2-like 1; P =5.7×10−15) and a locus on chromosome 2 (not near known genes) were associated with lower 16:1n-7 ( P =4.1×10−8).nnConclusions— Our findings provide novel evidence that common variations in genes with diverse functions, including protein-glycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of 4 fatty acids in the de novo lipogenesis pathway. These results expand our knowledge of genetic factors relevant to de novo lipogenesis and fatty acid biology.Background—Palmitic acid (16:0), stearic acid (18:0), palmitoleic acid (16:1n-7), and oleic acid (18:1n-9) are major saturated and monounsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis and are the main saturated and monounsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes mellitus and coronary heart disease. Methods and Results—Genome-wide association studies were conducted in 5 population-based cohorts comprising 8961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these 4 fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of ≥1 of these fatty acids. ALG14 (asparagine-linked glycosylation 14 homolog) polymorphisms were associated with higher 16:0 (P=2.7×10−11) and lower 18:0 (P=2.2×10−18). FADS1 and FADS2 (desaturases) polymorphisms were associated with higher 16:1n-7 (P=6.6×10−13) and 18:1n-9 (P=2.2×10−32) and lower 18:0 (P=1.3×10−20). LPGAT1 (lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0 (P=2.8×10−9). GCKR (glucokinase regulator; P=9.8×10−10) and HIF1AN (factor inhibiting hypoxia-inducible factor-1; P=5.7×10−9) polymorphisms were associated with higher 16:1n-7, whereas PKD2L1 (polycystic kidney disease 2-like 1; P=5.7×10−15) and a locus on chromosome 2 (not near known genes) were associated with lower 16:1n-7 (P=4.1×10−8). Conclusions—Our findings provide novel evidence that common variations in genes with diverse functions, including protein-glycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of 4 fatty acids in the de novo lipogenesis pathway. These results expand our knowledge of genetic factors relevant to de novo lipogenesis and fatty acid biology.

Genome-Wide Association Study of Plasma N6 Polyunsaturated Fatty Acids Within the Cohorts for Heart and Aging Research in Genomic Epidemiology ConsortiumCLINICAL PERSPECTIVE

Background—Omega6 (n6) polyunsaturated fatty acids (PUFAs) and their metabolites are involved in cell signaling, inflammation, clot formation, and other crucial biological processes. Genetic components, such as variants of fatty acid desaturase (FADS) genes, determine the composition of n6 PUFAs. Methods and Results—To elucidate undiscovered biological pathways that may influence n6 PUFA composition, we conducted genome-wide association studies and meta-analyses of associations of common genetic variants with 6 plasma n6 PUFAs in 8631 white adults (55% women) across 5 prospective studies. Plasma phospholipid or total plasma fatty acids were analyzed by similar gas chromatography techniques. The n6 fatty acids linoleic acid (LA), &ggr;-linolenic acid (GLA), dihomo-GLA, arachidonic acid, and adrenic acid were expressed as percentage of total fatty acids. We performed linear regression with robust SEs to test for single-nucleotide polymorphism–fatty acid associations, with pooling using inverse-variance–weighted meta-analysis. Novel regions were identified on chromosome 10 associated with LA (rs10740118; P=8.1×10−9; near NRBF2), on chromosome 16 with LA, GLA, dihomo-GLA, and arachidonic acid (rs16966952; P=1.2×10−15, 5.0×10−11, 7.6×10−65, and 2.4×10−10, respectively; NTAN1), and on chromosome 6 with adrenic acid after adjustment for arachidonic acid (rs3134950; P=2.1×10−10; AGPAT1). We confirmed previous findings of the FADS cluster on chromosome 11 with LA and arachidonic acid, and further observed novel genome-wide significant association of this cluster with GLA, dihomo-GLA, and adrenic acid (P=2.3×10−72, 2.6×10−151, and 6.3×10−140, respectively). Conclusions—Our findings suggest that along with the FADS gene cluster, additional genes may influence n6 PUFA composition.Background —Omega-6 (n6) polyunsaturated fatty acids (PUFAs) and their metabolites are involved in cell signaling, inflammation, clot formation, and other crucial biological processes. Genetic components, such as variants of fatty acid desaturase ( FADS ) genes, determine the composition of n6 PUFAs. nnMethods and Results —To elucidate undiscovered biologic pathways that may influence n6 PUFA composition, we conducted genome-wide association studies and meta-analyses of associations of common genetic variants with five plasma n6 PUFAs in 8,631 Caucasian adults (55% female) across five prospective studies. Plasma phospholipid or total plasma fatty acids were analyzed by similar gas chromatography techniques. The n6 fatty acids linoleic acid (LA), gamma-linolenic acid (GLA), dihomo-gamma-linoleic acid (DGLA), arachidonic acid (AA), and adrenic acid (AdrA) were expressed as % of total fatty acids. We performed linear regression with robust standard errors to test for SNP-fatty acid associations, with pooling using inverse-variance weighted meta-analysis. Novel regions were identified on chromosome 10 associated with LA (rs10740118, p-value = 8.1x10-9; near NRBF2 ); on chromosome 16 with LA, GLA, DGLA, and AA (rs16966952, p-value = 1.2x10-15, 5.0x10-11, 7.6x10-65, and 2.4x10-10, respectively; NTAN1 ); and on chromosome 6 with AdrA following adjustment for AA (rs3134950, p-value = 2.1x10-10; AGPAT1 ). We confirmed previous findings of the FADS cluster on chromosome 11 with LA and AA, and further observed novel genome-wide significant association of this cluster with GLA, DGLA, and AdrA (p-value = 2.3x10-72, 2.6x10-151, and 6.3x10-140, respectively). nnConclusions —Our findings suggest that along with the FADS gene cluster, additional genes may influence n6 PUFA composition.

Genome-Wide Association Study Identifies Novel Loci Associated With Concentrations of Four Plasma Phospholipid Fatty Acids in the De Novo Lipogenesis PathwayClinical Perspective

Background— Palmitic acid (16:0), stearic acid (18:0), palmitoleic acid (16:1n-7), and oleic acid (18:1n-9) are major saturated and monounsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis and are the main saturated and monounsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes mellitus and coronary heart disease.nnMethods and Results— Genome-wide association studies were conducted in 5 population-based cohorts comprising 8961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these 4 fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of ≥1 of these fatty acids. ALG14 (asparagine-linked glycosylation 14 homolog) polymorphisms were associated with higher 16:0 ( P =2.7×10−11) and lower 18:0 ( P =2.2×10−18). FADS1 and FADS2 (desaturases) polymorphisms were associated with higher 16:1n-7 ( P =6.6×10−13) and 18:1n-9 ( P =2.2×10−32) and lower 18:0 ( P =1.3×10−20). LPGAT1 (lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0 ( P =2.8×10−9). GCKR (glucokinase regulator; P =9.8×10−10) and HIF1AN (factor inhibiting hypoxia-inducible factor-1; P =5.7×10−9) polymorphisms were associated with higher 16:1n-7, whereas PKD2L1 (polycystic kidney disease 2-like 1; P =5.7×10−15) and a locus on chromosome 2 (not near known genes) were associated with lower 16:1n-7 ( P =4.1×10−8).nnConclusions— Our findings provide novel evidence that common variations in genes with diverse functions, including protein-glycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of 4 fatty acids in the de novo lipogenesis pathway. These results expand our knowledge of genetic factors relevant to de novo lipogenesis and fatty acid biology.Background—Palmitic acid (16:0), stearic acid (18:0), palmitoleic acid (16:1n-7), and oleic acid (18:1n-9) are major saturated and monounsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis and are the main saturated and monounsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes mellitus and coronary heart disease. Methods and Results—Genome-wide association studies were conducted in 5 population-based cohorts comprising 8961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these 4 fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of ≥1 of these fatty acids. ALG14 (asparagine-linked glycosylation 14 homolog) polymorphisms were associated with higher 16:0 (P=2.7×10−11) and lower 18:0 (P=2.2×10−18). FADS1 and FADS2 (desaturases) polymorphisms were associated with higher 16:1n-7 (P=6.6×10−13) and 18:1n-9 (P=2.2×10−32) and lower 18:0 (P=1.3×10−20). LPGAT1 (lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0 (P=2.8×10−9). GCKR (glucokinase regulator; P=9.8×10−10) and HIF1AN (factor inhibiting hypoxia-inducible factor-1; P=5.7×10−9) polymorphisms were associated with higher 16:1n-7, whereas PKD2L1 (polycystic kidney disease 2-like 1; P=5.7×10−15) and a locus on chromosome 2 (not near known genes) were associated with lower 16:1n-7 (P=4.1×10−8). Conclusions—Our findings provide novel evidence that common variations in genes with diverse functions, including protein-glycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of 4 fatty acids in the de novo lipogenesis pathway. These results expand our knowledge of genetic factors relevant to de novo lipogenesis and fatty acid biology.

Genome-wide association study identifies novel loci associated with concentrations of four plasma phospholipid fatty acids in the de novo lipogenesis pathway

Background— Palmitic acid (16:0), stearic acid (18:0), palmitoleic acid (16:1n-7), and oleic acid (18:1n-9) are major saturated and monounsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis and are the main saturated and monounsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes mellitus and coronary heart disease.nnMethods and Results— Genome-wide association studies were conducted in 5 population-based cohorts comprising 8961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these 4 fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of ≥1 of these fatty acids. ALG14 (asparagine-linked glycosylation 14 homolog) polymorphisms were associated with higher 16:0 ( P =2.7×10−11) and lower 18:0 ( P =2.2×10−18). FADS1 and FADS2 (desaturases) polymorphisms were associated with higher 16:1n-7 ( P =6.6×10−13) and 18:1n-9 ( P =2.2×10−32) and lower 18:0 ( P =1.3×10−20). LPGAT1 (lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0 ( P =2.8×10−9). GCKR (glucokinase regulator; P =9.8×10−10) and HIF1AN (factor inhibiting hypoxia-inducible factor-1; P =5.7×10−9) polymorphisms were associated with higher 16:1n-7, whereas PKD2L1 (polycystic kidney disease 2-like 1; P =5.7×10−15) and a locus on chromosome 2 (not near known genes) were associated with lower 16:1n-7 ( P =4.1×10−8).nnConclusions— Our findings provide novel evidence that common variations in genes with diverse functions, including protein-glycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of 4 fatty acids in the de novo lipogenesis pathway. These results expand our knowledge of genetic factors relevant to de novo lipogenesis and fatty acid biology.Background—Palmitic acid (16:0), stearic acid (18:0), palmitoleic acid (16:1n-7), and oleic acid (18:1n-9) are major saturated and monounsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis and are the main saturated and monounsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes mellitus and coronary heart disease. Methods and Results—Genome-wide association studies were conducted in 5 population-based cohorts comprising 8961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these 4 fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of ≥1 of these fatty acids. ALG14 (asparagine-linked glycosylation 14 homolog) polymorphisms were associated with higher 16:0 (P=2.7×10−11) and lower 18:0 (P=2.2×10−18). FADS1 and FADS2 (desaturases) polymorphisms were associated with higher 16:1n-7 (P=6.6×10−13) and 18:1n-9 (P=2.2×10−32) and lower 18:0 (P=1.3×10−20). LPGAT1 (lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0 (P=2.8×10−9). GCKR (glucokinase regulator; P=9.8×10−10) and HIF1AN (factor inhibiting hypoxia-inducible factor-1; P=5.7×10−9) polymorphisms were associated with higher 16:1n-7, whereas PKD2L1 (polycystic kidney disease 2-like 1; P=5.7×10−15) and a locus on chromosome 2 (not near known genes) were associated with lower 16:1n-7 (P=4.1×10−8). Conclusions—Our findings provide novel evidence that common variations in genes with diverse functions, including protein-glycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of 4 fatty acids in the de novo lipogenesis pathway. These results expand our knowledge of genetic factors relevant to de novo lipogenesis and fatty acid biology.