TABLE 2.
Individual study characteristics for included Genome-Wide Association Studies (Single nucleotide polymorphism-x- metabolite association) studies
| Authors, y (reference) | Choline type(s) reported | Outcome | Cohort or data source | Sample size (% female) | Mean age or range, y | Ethnicity | Relatedness | Key main text findings |
|---|---|---|---|---|---|---|---|---|
| Al-Khelaifi, 2019 [27] | Arachidonoylcholine stearoylcholine, betaine, choline phosphate, glycerophosphorylcholine (GPC), linoleoylcholine, oleoylcholine, choline, palmitoylcholine, palmitoloelycholine, PC, SMs | Genetic variation in metabolic individuality of endurance athletes. | Elite athletes cohort | 490 (13.5) | NR | Transethnic | None | Multiple SNPs were significantly associated with circulating choline, betaine, GPC, PCs, and SMs. |
| Aslibekyan, 2017 [28] | TMAO | Heritable determinants of plasma TMAO | Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) | 944 (48.83) | ∼48.75 | European | Families, siblings | The genome-wide study yielded 1 significant variant association with circulating TMAO at the genome-wide level, located in an intergenic region on chromosome 4. |
| Demirkan, 2015 [29] | TMAO/betaine, betaine | Novel gene-metabolite associations | Erasmus Rucphen Family (ERF) | 2415 (∼57) | 50.36 | Dutch | Families | Exome variants were not significantly associated with either circulating TMAO/betaine or betaine. |
| Draisma, 2015 [30] | Hydroxylacyloylsphingosylphosphocholine, LysoPCs PCs, SMs | Variation in human blood metabolite concentrations | Netherlands Twin Register (NTR) | 1196 (32.8%) | 53.09 | Netherlands | Twins | Genetic variants at the genome-wide level were associated with multiple forms of circulating LysoPCs, PCs, and SMs. |
| Queensland Institute of Medical Research(QIMR) cohort | 848 (48.9%) | 20.17 | Australia | None | ||||
| Twins United Kingdom (TwinsUK) | 1235 (96.4%) | 57.95 | United Kingdom | Twins | ||||
| Leiden Longevity Study (LLS) | 657 (50.4%) | 62.96 | Netherlands | Families | ||||
| Estonian Genome Center of University of Tartu Cohort (EGCUT) | 872 (38.8%) | 37.4 | Estoria | None | ||||
| Cooperative Health Research in the Region Augsburg F4 (KORA F4) | 1797 (51.1%) | 60.89 | Germany | None | ||||
| Erasmus Rucphen Family (ERF) Study | 940 (56.2%) | 48.30 | Netherlands | Families | ||||
| Cooperative Health Research in the Region Augsburg (KORA) | 1,182 (52.2%) | 49.02 | Germany | None | ||||
| Gieger, 2008 [31] | SMs, PCs | Genetic variants associated with 363 circulating metabolites | Cooperative Health Research in the Region Augsburg S3 (KORA S3) | 284 (0) | 35–79 | German | None | rs174548 in the FADS1 gene was significantly associated with circulating PCs and SMs. |
| Hartiala, 2014 [32] | TMAO | Genetic factors associated with plasma TMAO | Cleveland Clinic GeneBank study | 3865 (30.4%) | 64 | Non-Caucasian or Hispanic (based on eligibility criteria from https://clinicaltrials.gov/ct2/show/NCT00590200) | None | The genome-wide association for plasma identified 2 loci with suggestive evidence of association on chromosomes 1q23.3 and 2p12 with plasma TMAO concentrations. However, genotyping of the lead variants at these loci in replication subjects did not show an association with plasma TMAO concentrations. |
| Hartiala, 2016 [33] | Betaine | Genetic factors associated with plasma betaine and CAD | Cleveland Clinic GeneBank study | 8668 (29.7%) | 64 | Non-Caucasian or Hispanic (based on eligibility criteria from https://clinicaltrials.gov/ct2/show/NCT00590200) | None | 2 loci were significantly associated with circulating betaine on chromosomes 2q34 and 5q14.1. |
| Hicks, 2009 [34] | SM, dihydro-SM | Genetic variants associated with circulating (SM) and dihydro-SM concentration | Northern Swedish Population Health Study (NSPHS) | 656 (NR) | NR | Swedish | Families | Genetic variants across 23 candidate genes involved in sphingolipid-metabolizing pathways were significantly associated with circulating SM and dihydro-SM. |
| Hysi, 2022 [35] | Arachidonoylcholine, betaine, choline, GPCs, PC, SMs | Genomic regions associated with circulating metabolite concentrations. | National Institute for Health Research Bioresource cohort (NIHR UK) | 8809 (NR) | NR | European | Unsure | A SNP in the MYRF gene was strongly associated with circulating Arachidonoylcholine. Multiple SNPs were associated with circulating betaine, GPCs, and SMs. |
| Cooperative Health Research in the Region of Augsburg F4 (KORA F4) | 1768 (NR) | NR | German | None | ||||
| Illig, 2010 [36] | LysoPCs, PCs, SMs | Cardiovascular and metabolic disease-related SNP associations with metabolites | Cooperative Health Research in the Region of Augsburg S4 (KORA S4) | 1809 (∼52.1) | 32–81 | German | None | Top cardiovascular and metabolic disease-related SNPs were significantly associated with numerous circulating LysoPCs, PCs, and SMs. |
| Twins United Kingdom (TwinsUK) | 422 (NR) | NR | British | The authors selected unrelated individuals for analysis | ||||
| Kettunen, 2016 [37] | SMs, PCs | SNPs associated with circulating cardiovascular disease risk metabolites, focusing on the LPA locus. | Estonian Genome Center of University of Tartu Cohort (EGCUT) | 3287 (46.3) | 58 | Estonian | None | No significant associations were found between SNPs and circulating PCs or SMs. |
| Erasmus Rucphen Family Study (ERF) | 2118 (48.2) | 58 | Dutch | Families | ||||
| Finnish Twin Cohort(FTC) | 664 (23.9) | 50 | Twins | |||||
| Dietary, Lifestyle, and Genetic determinants of Obesity and Metabolic syndrome study [DILGOM (FR97, a subsample of Finnish National study (FINRISK) 1997)] | 3661 (45.3) | 55 | Finnish | None | ||||
| Genetic Predisposition of Coronary Heart Disease in Patients Verified with Coronary Angiogram(COROGENE) | 828 (53.2) | 54 | Finnish | None | ||||
| Genetics of METabolic Syndrome (GenMets) | 572 (55.8) | 57 | Finnish | None | ||||
| Helsinki Birth Cohort Study (HBCS) | 708 (61.3) | 60 | Finnish | None | ||||
| Cooperative Health Research in the Region of Augsburg (KORA) | 1745 (60.9) | 52 | German | None | ||||
| Leiden Longevity Study (LLS) | 2227 (59.2) | 54 | Dutch | Families | ||||
| Netherlands Twin Register (NTR) | 1192 (38.8) | 64 | Dutch | None | ||||
| Northern Finland Birth Cohort 1966 (NFBC 1966) | 4709 (31.2) | 51 | Finnish | None | ||||
| Finnish National study (FINRISK) subsample of incident cardiovascular cases and controls (Personalized Responses to Dietary Composition Trial-Cardiovascular Disease [PREDICT-CVD]) | 374 (47.5) | 37 | Finnish | None | ||||
| Estonian Genome Center of University of Tartu Cohort (EGCUT sub-cohort, PROTE) | 597 (38.3) | 51 | Estonian | None | ||||
| The Cardiovascular Risk in Young Finns Study (YFS) | 2390 (37.7) | 54 | Finnish | None | ||||
| Kettunen, 2012 [38] | Choline, PC | SNP associations with 216 serum metabolites | Northern Finland Birth Cohort 1966 (NFBC1966) | 4703 (31.0) | 51 | Finnish | None | Multiple SNPs were significantly associated with circulating choline and PC. |
| The Cardiovascular Risk in Young Finns Study (YFS) | 1904 (37.7) | 54 | Finnish | None | ||||
| Helsinki Birth Cohort Study (HBCS) | 708 (61.3) | 60 | Finnish | None | ||||
| Genetics of METabolic Syndrome (GenMets) subsample of Finnish Health2000 examination survey | 572 (55.8) | 57 | Finnish | None | ||||
| The Dietary, Lifestyle, and Genetic determinants of Obesity and Metabolic Syndrome (DILGOM) | 443 (50.1) | 56 | Finnish | None | ||||
| Finnish Twin cohorts 12 and 16 (FinnTwin12 and FinnTwin16) | 1269 (23.9) | 55 | Finnish | None | ||||
| Lee, 2016 [39] | LysoPC | Genetic variants associated with metabolomics identified T2D-related metabolites | Korea Association Resource Survey 2 (KARE S2) cohort | 2240 (∼55.2%) | ∼56 | South Korean | None | Genetic variants were not associated with circulating LysoPC. |
| Li, 2018 [40] | LysoPC a C20:4, PC ae C38:4, PC ae C38:5, PC ae C36:5, PC aa C36:4, PC aa C36, PC aa C28:1, PC ae C32:1, SM (OH) C14:1 | Genetic variants of the concentrations of 139 serum metabolites and 41 urine metabolites in people with chronic kidney disease. | German Chronic Kidney Disease (GCKD) Study | 1143 (37%) | 56 | German | None | One genetic variant at TMEM258 was significantly associated with LysoPCs. Eight genetic variants at MYRF, TMEM258, FADS1, FADS2, SGPP1, SYNE2, and TMEM229B were significantly associated with circulating PCs. One genetic variant at SGPP1 and SYNE2 was significantly associated with circulating SMs. |
| Li-Gao, 2021 [41] | PCs and other cholines, SMs, and total choline | Genetics and heritability of plasma metabolomic measures | Netherlands Epidemiology of Obesity (NEO) study | 6671 [5705 analyzed (47.49)] | 45–65 | Dutch | None | Multiple SNPs were significantly associated with circulating PCs and other cholines, SMs, and total choline. |
| Long, 2017 [42] | Betaine, choline, PCs, SMs | Abnormal blood metabolic phenotypes | Twins United Kingdom (TwinsUK) | 1960 (96.6%) | Median = 58, range = 32–87 | European descent | Twins | SNPs were not associated with circulating betaine or choline. Multiple SNPs were significantly associated with multiple forms of circulating PCs and SMs. |
| Richardson, 2022 [43] | Cholines, SMs | Lipid-modifying therapeutic targets on the blood metabolome and subsequent CVD risk reduction. | UKBiobank | 115,082 | 40–71 | European | None | Multiple SNPs were significantly associated with circulating cholines and SMs. |
| Coronary Artery Disease Genome-Wide Replication and Meta-analysis (CARDIoGRAM) plus the Coronary Artery Disease Genetics (CARDIoGRAMplusC4D) Consortium | CARDIoGRAMplusC4D consortium | 60,801 CAD cases (NR); 123,504 controls (NR) | NR | Transethnic | ||||
| Diabetes Meta-Analysis of Trans-Ethnic Association Studies (DIAMANTE) Consortium | DIAMANTE consortium | 74,124 T2D cases (NR); 824,006 controls (NR) | NR | European | ||||
| Rhee, 2013 [44] | PCs, LysoPCs, SMs | Relative contributions of inherited factors on the plasma metabolome | Framingham Heart Study (FHS) | 2076 (51%) | 55 | European descent | Spouses | SNPs in the FADS1-3 locus were significantly associated with multiple circulating PCs and LysoPCs. One SNP in the GCKR locus was associated with circulating PC 34:3 and PC 32:2. SNPs in the SYNE2 and PDE4D genes were associated with circulating SM 14:0 and 24:1, respectively. |
| Rhee, 2016 [45] | Cholines, PCs, SMs | Genetic variants associated with the plasma metabolome | Framingham Heart Study (FHS) | 2076 (51%) | 55 | European descent | Spouses | No genetic variants were significantly associated with circulating choline metabolites. |
| Atherosclerosis Risk in Communities (ARIC) Study | 1528 (NR) | Range = 45–64 | European descent | None | ||||
| Shin, 2014 [46] | Betaine, palmitoyl SM | Genetic loci influencing the human metabolome | Twins United Kingdom (TwinsUK) | 6056 (93%) | 53 | British | Twins | SNPs in CBS, CPS1, and BHMT (rs16876394) loci were significantly associated with circulating betaine. One SNP in the SPTLC3 locus was significantly associated with circulating palmitoyl-SM. |
| Cooperative Health Research in the Region of Augsburg (KORA) study (F4 and S4) | 1768 (50%) | 61 | German | None | ||||
| Surendran, 2022 [47] | Choline, choline phosphate, GPC, PC, SMs | Genetic architecture of over 900 metabolites | Efficiency and safety of varying the frequency of whole blood donation (INTERVAL) study | 8455 (48.8%) | 44 | European descent | Authors excluded related individuals in analyses | Multiple SNPs were significantly associated with circulating choline, choline phosphate, GPCs, PC, and SMs in the multi-cohort meta-analysis. |
| European Prospective Investigation into Cancer and Nutrition(EPIC) -Norfolk study | 11,539 (53.3%) total= 5841 (discovery) plus 5698 (validation) | 59.8 | European descent | Authors excluded related individuals in analyses | ||||
| Tabassum, 2019 [48] | Total lysoPC, lysoPC (14:0;0), lysoPC (16:1;0), PC (16:0;0–16:0;0), PC (16:0;0–16:1;0), PC (16:0;0–18:1;0), PC-ether (16:1;0–16:0;0), PC-ether 18:2;0–18:1;0, SM (32:1;2), SM (34:0;2), SM (38:2;2) | Genetic variants associated with 141 lipid species | The European Multicenter Study on Familial Dyslipidemias in Patients with Premature Coronary Heart Disease (EUFAM) | 1039 (NR) | NR | Finnish | Families | Intronic variant rs151223356 near ROCK1 was significantly associated with circulating short acyl-chain lysoPC (14:0,0). Variants at DDX43, COL26A1, SYT1, and MAF were associated with circulating LysoPCs. SNPs near BLK, COL5A1, TNFAIP3, GATM, and RBFOX3 were significantly associated with circulating PCs. New associations of SNPs near GLTPD2, SYNE2, and CERS4 with circulating SM (34:0;2) were discovered. |
| The Finnish National Study (FINRISK) | 1142 (NR) | NR | Finnish | None | ||||
| Tahir, 2022 [49] | Betaine, predicted LysoPC, SMs | To identify novel locus-metabolite associations in Black individuals. | Jackson Heart Study(JHS) | 2466 (62) | 56 | African American | Families | A SNP in the SLC6A12 gene was significantly associated with circulating betaine. Rs334 (associated with the sickle mutation) was significantly associated with a circulating metabolite predicted to be LysoPC. Multiple SNPs were significantly associated with multiple circulating SMs. |
| Tukiainen, 2012 [50] | Choline, PC, SM | A set of 440,807 genotyped and imputed genetic markers are associated with 216 metabolic variables. | Northern Finland Birth Cohort 1966 | 4703 (31) | 51 | Finnish | None | No SNPs were significantly associated with choline/choline metabolites. |
| The Cardiovascular Risk in Young Finns Study (YFS) | 1904 (37.7) | 54 | Finnish | None | ||||
| Helsinki Birth Cohort Study | 708 (61.3) | 60 | Finnish | None | ||||
| Genetics of METabolic Syndrome (GenMets) subsample of Finnish Health2000 examination survey | 572 (55.8) | 57 | Finnish | None | ||||
| The Dietary, Lifestyle, and Genetic determinants of Obesity and Metabolic Syndrome (DILGOM) | 443 (50.1) | 56 | Finnish | None | ||||
| Yet, 2016 [51] | 1-arachidonoylglycerophosphocholine, glycerolphosphocholine, PCs, LysoPCs, SMs | SNPS associated with high-throughput metabolic profiles | Twins United Kingdom (TwinsUK) | 1001 (NR) | NR | British | Twins | SNPs were significantly associated with circulating LysoPC a C20:4 and 1-arachidonoyl-GPC across Biocrates and Metabolon platforms. Metabolite associations with genetic variants at the SGPP1 locus did not match in name for PC aa C28:1 (Biocrates) and 1-stearoylglycerol (Metabolon). |
| Yousri, 2018 [52] | Choline, betaine, GPC, SMs | Loci affecting metabolites and metabolite ratios | Human subjects recruited from Hamad Medical Corporation (HMC) and HMC Primary Health Care Centers in Doha, Qatar | 91 (45%) | 50.1 | Qatari | Authors accounted for relatedness in analyses | No SNPs were significantly associated with circulating choline or choline-related metabolites. |
| Yu, 2014 [53] | Betaine, GPCs, SMs | Common genetic variants influencing the metabolome in African Americans | The Atherosclerosis Risk in Communities (ARIC) Study | 15,792 (65.2) | 52.6 | African American | None | No SNPs were significantly associated with any circulating choline-related metabolites. |
CAD, coronary artery disease; CVD, cardiovascular disease; LysoPCs, lysophosphatidylcholine; PC, phosphatidylcholine; SM, sphingomyelin; T2D, type II diabetes; TMAO, trimethylamine N-oxide; BHMT, betaine-homocysteine S-methyltransferase; CBS, cystathionine beta synthase; CPS1, carbamoyl-phosphate synthase 1; GCKR, glucokinase regulator; LPA, lipoprotein(A); MYRF, myelin regulatory factor; NR, not reported; PDE4D; PROTE, EGCUT sub-cohort; ROCK1, rho associated coiled-coil containing protein kinase 1; SGPP1, sphingosine-1-phosphate phosphatase 1; SPTLC3, serine palmitoyltransferase long chain base subunit 3; SYNE2, spectrin repeat containing nuclear envelope protein 2; TMEM, transmembrane protein.