Table 4.
Number of Candidate–Gene Association Studies on Each Gene Locus–Disease Association (per HuGE Navigator) and Comments Regarding Previous Knowledge on the Loci Containing the Uncommon Variants as They Appear in the Eligible GWAS
| Disease/Trait | Reported Gene(s) | Uncommon Variant(s) | No. of Studies Until December of the Year Before the First GWAS Proposal | Total No. of Studies on Gene–Phenotype to Date | Comments on Gene Locus in Text |
| ALL | KRTHB5 | rs2089222-A | 0 | 0 | No comment |
| AIDS progression | HCP5, MICB, MCCD1, BAT1, LTB, TNF | rs2395029-G | 1 for HCP, 1 for TNF, 0 for the rest | 1 | HCP5 was previously identified by the GWAS-based Euro-CHAVI cohort and also proposed by candidate–gene association studies |
| C6orf48 | rs9368699-C | 0 | 0 | No comment | |
| Blue vs. green eyes | OCA2 | rs1667394-A | 0 | 1 | Previously reported to be associated with albinism, eye color, hair color, and skin pigmentation; OCA2 mutations are known to be a major cause for albinism; OCA2 has been discovered in linkage studies. |
| Freckles | MC1R | rs1805007-T | 0 | 3 | It was known by previous reports; previously documented mutations in MC1R |
| BMD (lumbar spine) | AKAP11 | rs180851-G, rs7326472-G, rs12854504-G, rs7998154-T | 0 | 0 | No comment |
| TNFSF11 | rs6561055-A, rs17639156-G | 3 | 11 | No comment | |
| Cognitive performance | HCCS | rs5934953-C | 0 | 0 | No comment |
| Crohn's disease | NOD2 | rs2066844-T, rs2066845-C, rs2066847-C | 176 | 301 | NOD2 is a previously known Crohn's disease locus. |
| LRRK2, MUC19 | rs11175593-T | 1 for MUC19, 0 for LRRK2 | 1 for MUC19, 0 for LRRK2 | LRRK2: evidence from a previous cell study; MUC19: evidence from a previous animal study | |
| HDL cholesterol | HNF4A | rs1800961-C | 3 | 5 | Function in humans has previously been studied; although mice lacking either Hnf4a or Hnf1a have altered plasma cholesterol levels, there has been only modest evidence to date connecting these genes to either HDL or LDL cholesterol concentrations in humans. |
| ABCA1 | rs9282541-T | 34 | 53 | It is a well-recognized association. | |
| Hematocrit | HFE | rs1800562-A | 3 | 4 | Mutations in the HFE gene are already known to underlie hereditary hemochromatosis. The HFE gene induces expression of the iron-regulatory hormone hepcidin. |
| Hemoglobin | HFE | rs1800562-A | 17 | 21 | Mutations in the HFE gene are already known to underlie hereditary hemochromatosis. The HFE gene induces expression of the iron-regulatory hormone hepcidin. |
| LDL cholesterol | PCSK9 | rs11591147-G | 10 | 26 | Prior evidence for association with LDL cholesterol concentrations; has also been shown to cause Mendelian syndromes or to harbor multiple rare alleles that contribute to trait variation |
| MCH | SLC17A3 | rs1408272-G | 0 | 0 | No comment |
| MCV | HFE | rs1800562-A | 3 | 5 | HFE is known to be associated with iron homeostasis. |
| NSCL | Intergenic | rs17085106-T | N/A | N/A | |
| Nasopharyngeal carcinoma | ITGA9 | rs189897-A | 0 | 1 | The gene is located at the chromosomal 3p22-21.3 segment, which is known to be commonly deleted in various types of carcinoma including NPC. A linkage study also mapped an NPC susceptibility locus to chromosome 3p21.31-21.2, indicating that the genes in this region are crucial for the formation of NPC. |
| rs197757-T | 0 | 1 | |||
| Panic disorder | TMEM16B a | rs12579350-A | 0 | 1 | No comment |
| PKP1 | rs860554-T | 0 | 1 | The gene has an important role in the cytoskeleton–cell membrane interaction. The protein of PKP1, plackoglobin, acts as linker molecules at adherence junctions and desmosome at the plasma membrane. | |
| Prostate cancer | Intergenic | rs16901979-A | N/A | N/A | |
| Primary biliary cirrhosis | C6orf10 | rs2395148-A | 0 | 0 | No comment |
| ALP | PDZRN4, CNTN1 | rs1880887-C | 0 | 1 | No comment (locus found only in supplement) |
| fT3 | HS3ST3B1 | rs3848445-C | 0 | 1 | No comment (locus found only in supplement) |
| Psoriasis | HLA-C | rs2395029-C | 57 | 65 | Strongest association with this region is consistent with previous results from our group and others. |
| Response to treatment for ALL | ST8SIA6 | rs359312-T | 0 | 0 | No comment |
| Response to antipsychotic therapy | Intergenic | rs17022444-G | N/A | N/A | |
| Intergenic | rs7669317-C | N/A | N/A | ||
| SLE | TNFAIP3 | rs5029939-G | 0 | 10 | Previously unreported for SLE susceptibility; recent reports for influencing rheumatoid arthritis risk. This GWAS identifies TNFAIP3 as a new susceptibility locus in SLE. |
| SLE | TNFAIP3 | rs2230926-C | 0 | 10 | Reported by previous GWAS |
| Tanning | MATP | rs35391-T | 0 | 0 | SNPs in MATP were previously evaluated in the GWAS of natural hair color by our group. Three SNPs in the MATP gene have been associated with human pigmentation. |
| Triglycerides | APOA1, APOC3, APOA4, APOA5 | rs662799-G | 118 for APOA1, APOC3, APOA4, APOA5 | 165 combined for APOA1, APOC3, APOA4, APOA5 | These loci have been previously implicated in lipid metabolism. |
| Triglycerides | APOA1, APOC3, APOA4, APOA5, DSCAML1 | rs10892151-A | 118 for APOA1, APOC3, APOA4, APOA5 | 165 combined for APOA1, APOC3, APOA4, APOA5 | APOA1, APOC3, APOA4, APOA5 is a cluster of more likely candidate genes, given the established key roles of their products in lipid metabolism. |
| Type 1 diabetes | COBL | rs4948088-C | 0 | 0 | No comment |
| Type 2 diabetes | TCF7L2 | rs7903146-T | 14 | 140 | It was reported by previous studies. |
Abbreviations: AIDS, acquired immunodeficiency syndrome; ALL, acute lymphoblastic leukemia; ALP, alkaline phosphatase; BMD, bone mineral density; fT3, free triiodothyronine; GWAS, genome-wide association study(ies); HDL, high density lipoprotein; HuGE, Human Genome Epidemiology; LDL, low density lipoprotein; MCH, mean corpuscular hemoglobin; MCV, mean corpuscular volume; N/A, nonapplicable because the variants are in intergenic regions; NPC, nasopharyngeal carcinoma; NSCL, nonsyndromic cleft lip with or without cleft palate; SLE, systemic lupus erythematosus; SNP, single-nucleotide polymorphism.
a
TMEM16B was found as ANO2 in HuGE Navigator.