From: Complex genetic diseases: controversy over the Croesus code
Disease type | Locus | Allele | Trait | Frequency | Effect | Comments |
---|---|---|---|---|---|---|
(a) Common disease/common variant hypothesis | ||||||
Cardiovascular | APOE | *E4 | Alzheimer | 0.10-0.15 | Early onset | Allele present in primates and all world |
 |  |  | disease | (Caucasian) |  | populations; possible interaction with |
 |  |  |  |  |  | dietary fats; may account for 20% of |
 |  |  |  |  |  | Alzheimer disease |
 |  |  | Age-related | 0.10-0.15 | Decreased risk | Well-established protective effect on |
 |  |  | macular |  |  | age-related macular degeneration |
 |  |  | degeneration |  |  |  |
 |  |  | Cardiovascular | 0.10-0.15 | Increased risk | Accounts for 10-16% of plasma |
 |  |  | disease |  |  | cholesterol variance (western |
 |  |  |  |  |  | populations); increases risk of |
 |  |  |  |  |  | cardiovascular disease (odds ratio |
 |  |  |  |  |  | approximately 1.5) |
 | F5 | R506Q | Venous | 0.02-0.08 | Increased risk | Carriers have around 10% lifetime risk |
 |  |  | thrombosis |  |  | for significant venous thrombosis |
Metabolic/ | PPARG | P12A | Type 2 diabetes | 0.85 | Increased risk | Relative risk 1.25 |
nutritional | Â | Â | mellitus | (Caucasian) | Â | Â |
 | CAPN10 | Haplotypes | Type 2 diabetes | 0.03-0.29 (low | Increased risk in | Complex risk haplotypes that may |
 |  | 112 and 121 | mellitus | to high risk | 121/112 haplotype | include several SNPs, including |
 |  |  |  | populations) | heterozygotes | CAPN10-g.4852G/A (UCSNP-43) |
 | HFE | C282Y | Haemochromatosis | 0.05 | Around 40% risk | High frequency in Caucasians, low in |
 |  |  |  | (Caucasian) | for homozygotes | Asiatics (suggesting admixture), so it may |
 |  |  |  |  |  | be a recent mutation (less than 50,000 |
 |  |  |  |  |  | years ago) |
Cancer | ELAC2 | S217L | Prostate cancer | 0.30 and 0.04 | Increased risk | Odds ratio 2.4-3.1 |
 |  | and A541T |  | (Caucasian) |  |  |
 | BRCA2 | N372H | Breast cancer | 0.22-0.29 | Increased risk | Relative risk = 1.31 for HH compared to |
 |  |  |  | (Caucasian) |  | NN genotypes |
Infectious/ | MHC class I | HLA-B*2702, | Ankylosing | 0.09 | Increased risk | Odds ratio approximately 170, mechanism |
inflammatory | Â | 04, 05 | spondylitis | (Caucasian) | Â | unclear; also associated with reactive |
 |  |  |  |  |  | arthritis and uveitis; about 2% of B27- |
 |  |  |  |  |  | positive carriers develop ankylosing |
 |  |  |  |  |  | spondylitis |
 | MHC class II | DQB1*0302- | Type 1 diabetes | 0.05 | Increased risk | Around 10% of heterozygotes for these |
 |  | DRB1*0401/ | mellitus | (European) |  | high risk haplotypes develop type 1 |
 |  | DQB1*0201- |  |  |  | diabetes mellitus; relative risk |
 |  |  |  |  |  | approximately 20 |
 |  | DRB1*03 |  |  |  |  |
 | IL12B | 3' UTR | Type 1 diabetes | 0.79 | Increased risk | Interaction with HLA; increased |
 |  | allele 1 | mellitus | (Caucasian) |  | expression of IL12B in vitro |
 | G6PD | A- | G6PD deficiency | Approximately | Decreased risk of | High allele frequency proposed to be |
 |  | (V68M/N126D) |  | 0.20 (West | severe malaria | due to balancing selection |
 |  |  |  | African) |  |  |
 | HBB | HbC (E6K) | Anaemia | 0.09 (West | Decreased risk of | High allele frequency proposed to be |
 |  |  | (homozygotes) | African) | severe malaria | due to balancing selection |
 | CCR5 | Δ32-CCR5 | HIV-1 | 0.09 | Decreased HIV-1 | Recent origin - estimated approximately |
 |  |  | transmission | (Caucasian) | transmission | 700 years ago [13] |
Developmental | PDGFRA | Promoter | Neural tube | 0.23 | Increased risk for | At least six polymorphic sites within |
 |  | H1/H2α | defect | (Caucasian) | sporadic neural | each haplotype |
 |  | haplotypes |  |  | tube defect |  |
(b) Multilocus/multiallele hypothesis | ||||||
Cardiovascular | LDLR | > 735 alleles | Coronary artery | All rare, except in | Increased risk of | Â |
 |  |  | disease | isolate or founder | coronary artery |  |
 |  |  |  | populations | disease |  |
 | APOB | > 24 alleles | Coronary artery | R3500Q 0.002, | Increased risk of | Single common R3500Q allele |
 |  |  | disease | remainder rare | coronary artery |  |
 |  |  |  |  | disease |  |
Cancer | BRCA1 | > 483 alleles | Familial breast- | All rare, except in | Increased risk | Â |
 |  |  | ovarian cancer | isolate or founder |  |  |
 |  |  |  | populations |  |  |
 | BRCA2 | > 404 alleles | Familial breast | All rare, except in | Increased risk | Common N372H allele (frequency |
 |  |  | cancer | isolate or founder |  | approximately 0.25) with relative |
 |  |  |  | populations |  | risk 1.31 |
 | MLH1 | > 143 alleles | Hereditary non- | All rare | Increased risk |  |
 |  |  | polyposis colorectal |  |  |  |
 |  |  | cancer (HNPCC) |  |  |  |
 | MSH2 | > 108 alleles | Hereditary non- | All rare | Increased risk |  |
 |  |  | polyposis colorectal |  |  |  |
 |  |  | cancer (HNPCC) |  |  |  |
 | P53 | > 144 alleles | Multiple cancers | All rare | Increased risk |  |
Neurosensory | ABCA4 | > 350 alleles | Stargardt disease, | Most rare, G863A | Increased risk | Â |
 |  |  | retinitis pigmentosa | allele approximately |  |  |
 |  |  |  | 0.014 (Europeans) |  |  |
 | RHO | > 88 alleles | Retinitis pigmentosa, | All rare | Increased risk |  |
 |  |  | congenital stationary |  |  |  |
 |  |  | night blindness |  |  |  |
 | GJB2 | > 45 alleles | Non-syndromic | Most rare, 30delG | Increased risk | 30delG absent from non-European |
 |  |  | deafness | allele around 0.015 |  | populations |
 |  |  |  | (Europeans) |  |  |
Metabolic/ | CFTR | > 963 alleles | Cystic fibrosis | Most rare, | Â | Â |
nutritional |  |  |  |  | ΔF508 accounts for | Increased risk ΔF508 allele recent |
 |  |  |  |  | approximately 70% | -estimated to have arisen 3,000 |
 |  |  |  |  | of cystic fibrosis | years ago [14] |
 |  |  |  |  | alleles in Caucasians |  |