Genetic structure of five susceptibility gene regions for coronary artery disease: disequilibria within and among regions

Abstract We analyzed two-locus disequilibria for 16 polymorphic loci of seven susceptibility genes for coronary artery disease located in five chromosomal regions distributed across four chromosomes. Included were the genes coding for apolipoprotein B (ApoB, chromosome 2, four marker loci), lipoprotein lipase (LPL, chromosome 8, three marker loci), apolipoproteins AI, CIII, AIV (ApoAI–CIII–AIV, chromosome 11, three marker loci), apolipoprotein E (ApoE, chromosome 19, two marker loci), and the low density lipoprotein receptor (LDLR, chromosome 19, four marker loci). Our sample included 540 unrelated individuals from the Rochester, Minn. population. There were no statistically significant deviations of single-locus genotypes from Hardy-Weinberg equilibrium. The strongest associations within genes were for composite diallelic disequilibria; 17/19 were significant (13 at Pr <0.001, 1 at Pr <0.01, 3 at Pr <0.05). These observations suggest marker alleles within genes have a shared evolutionary history reflected by disequilibria that have not been dissipated by recombination. Disequilibrium was not generally concordant with the physical orderings of markers. Only two significant higher-order disequilibria were observed although 12 triallelic disequilibria were at maximum possible values. We observed 19 statistically significant disequilibria (Pr <0.05; 4 composite diallelic, 13 triallelic, and 2 quadriallelic) between 101 pairs of marker loci, where each locus in a pair was from a different unlinked region. These unexpected results are most likely explained by recent historical factors, including worldwide population expansion and amalgamation with continuous admixture, that influence the genetic structure (organization of alleles and non-alleles into genotypes) of a population. We conclude that disequilibria between loci from unlinked regions may be more extensive than is commonly assumed. Our findings also suggest that it is, on average, at least 15 times more likely to not detect significant disequilibrium among unlinked loci when it is really present than to make a false positive inference. Disequilibria between functional loci within or between regions will impact estimates of genetic variance associated with particular functional mutations within a susceptibility gene region.

[1]  E. Boerwinkle,et al.  A cladistic analysis of phenotypic associations with haplotypes inferred from restriction endonuclease mapping. I. Basic theory and an analysis of alcohol dehydrogenase activity in Drosophila. , 1987, Genetics.

[2]  K H Buetow,et al.  A comprehensive human linkage map with centimorgan density. Cooperative Human Linkage Center (CHLC). , 1994, Science.

[3]  C. Sing,et al.  A Consideration of the Power of the χ2 Test to Detect Inbreeding Effects in Natural Populations , 1970, The American Naturalist.

[4]  C. Sing,et al.  Distribution of sodium-lithium countertransport and blood pressure in Caucasians five to eighty-nine years of age. , 1989, Hypertension.

[5]  TaqI polymorphism in the human LDL receptor gene. , 1987, Nucleic acids research.

[6]  K. Svenson,et al.  Organization of the human lipoprotein lipase gene and evolution of the lipase gene family. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[7]  E. Boerwinkle,et al.  Haplotype structure and population genetic inferences from nucleotide-sequence variation in human lipoprotein lipase. , 1998, American journal of human genetics.

[8]  C. Zapata,et al.  Gametic disequilibrium and physical distance. , 1995, American journal of human genetics.

[9]  E. Boerwinkle,et al.  A three codon insertion/deletion polymorphism in the signal peptide region of the human apolipoprotein B (APOB) gene directly typed by the polymerase chain reaction. , 1989, Nucleic acids research.

[10]  C. Sing,et al.  A cladistic analysis of phenotypic associations with haplotypes inferred from restriction endonuclease mapping. IV. Nested analyses with cladogram uncertainty and recombination. , 1993, Genetics.

[11]  Soumitra Ghosh.  Probability and complex disease genes , 1995, Nature Genetics.

[12]  P. Brink,et al.  A DNA polymorphism in the human low-density lipoprotein receptor gene. , 1986, South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde.

[13]  B. Weir,et al.  6. Complete Characterization Of Disequilibrium At Two Loci , 1989 .

[14]  C. Fielding,et al.  A protein cofactor of lecithin:cholesterol acyltransferase. , 1972, Biochemical and biophysical research communications.

[15]  E. Schaefer,et al.  Lipoprotein apoprotein metabolism. , 1978, Journal of lipid research.

[16]  D. Rao,et al.  Linkage disequilibrium between DNA markers at the low‐density lipoprotein receptor gene , 1990, Genetic epidemiology.

[17]  C. Sing,et al.  Effects of polymorphisms in apolipoproteins E, A-IV, and H on quantitative traits related to risk for cardiovascular disease. , 1991, Arteriosclerosis and thrombosis : a journal of vascular biology.

[18]  J. Scott,et al.  RFLP for the human apolipoprotein B gene: IV;MspI. , 1985, Nucleic acids research.

[19]  W. Weidman,et al.  Genetic determination of plasma apolipoprotein AI in a population-based sample. , 1989, American journal of human genetics.

[20]  Charles R.scriver,et al.  The Metabolic basis of inherited disease , 1989 .

[21]  A. Kessling,et al.  A study of DNA polymorphisms around the human apolipoprotein Al gene in hyperlipidaemic and normal individuals , 1985, Clinical genetics.

[22]  C. Sing,et al.  Influences of common variants of apolipoprotein E on measures of lipid metabolism in a sample selected for health. , 1991, Arteriosclerosis and thrombosis : a journal of vascular biology.

[23]  G. Assmann,et al.  Bst NI (Eco RII) RFLP in the lipoprotein lipase gene (LPL). , 1988, Nucleic acids research.

[24]  C. Sing,et al.  Association between common alleles of the low-density lipoprotein receptor gene region and interindividual variation in plasma lipid and apolipoprotein levels in a population-based sample from Rochester, Minnesota , 1996, Human Genetics.

[25]  R. Pease,et al.  Structure of the human apolipoprotein B gene. , 1986, The Journal of biological chemistry.

[26]  E. Wijsman.  A deductive method of haplotype analysis in pedigrees. , 1987, American journal of human genetics.

[27]  E. Thompson,et al.  Allelic disequilibrium and allele frequency distribution as a function of social and demographic history. , 1997, American journal of human genetics.

[28]  J. Ruidavets,et al.  Extended haplotypes and linkage disequilibrium between 11 markers at the APOA1-C3-A4 gene cluster on chromosome 11. , 1991, American journal of human genetics.

[29]  E. Thompson,et al.  The detection of linkage disequilibrium between closely linked markers: RFLPs at the AI-CIII apolipoprotein genes. , 1988, American journal of human genetics.

[30]  G. FitzGerald,et al.  Two polymorphisms in the human lipoprotein lipase (LPL) gene. , 1987, Nucleic acids research.

[31]  S. Tanksley.  Mapping polygenes. , 1993, Annual review of genetics.

[32]  P. Brown,et al.  Genomics and human disease—variations on variation , 1998, Nature Genetics.

[33]  B S Weir,et al.  Likelihood methods for locating disease genes in nonequilibrium populations. , 1995, American journal of human genetics.

[34]  H. H. Hobbs,et al.  AvaII polymorphism in the human LDL receptor gene , 1987, Nucleic Acids Res..

[35]  C. Sing,et al.  Analysis of multilocus genetic systems in Tecumseh, Michigan. II. Consideration of the correlation between nonalleles in gametes. , 1972, American journal of human genetics.

[36]  J. Stephens,et al.  Mapping by admixture linkage disequilibrium in human populations: limits and guidelines. , 1994, American journal of human genetics.

[37]  C. Sing,et al.  Genetic structure and the search for genotype-phenotype relationships: an example from disequilibrium in the Apo B gene region. , 1991, Genetics.

[38]  W. Ewens,et al.  The transmission/disequilibrium test: history, subdivision, and admixture. , 1995, American journal of human genetics.

[39]  C. Sing,et al.  Role of the apolipoprotein E polymorphism in determining normal plasma lipid and lipoprotein variation. , 1985, American journal of human genetics.

[40]  N Risch,et al.  The Future of Genetic Studies of Complex Human Diseases , 1996, Science.

[41]  D. Galton,et al.  Pvu-II RFLP at the human lipoprotein lipase (LPL) gene locus. , 1988, Nucleic acids research.

[42]  B S Weir,et al.  Disequilibrium on human chromosome 11p , 1986, Genetic epidemiology. Supplement.

[43]  P. Hedrick,et al.  Gametic disequilibrium measures: proceed with caution. , 1987, Genetics.

[44]  C. Sing,et al.  Biological complexity and strategies for finding DNA variations responsible for inter-individual variation in risk of a common chronic disease, coronary artery disease. , 1992, Annals of medicine.

[45]  C. Sing,et al.  Estimation of Hardy-Weinberg and pairwise disequilibrium in the apolipoprotein AI-CIII-AIV gene cluster. , 1991, American journal of human genetics.

[46]  B. Weir,et al.  Are moment bounds on the recombination fraction between a marker and a disease locus too good to be true? Allelic association mapping revisited for simple genetic diseases in the Finnish population. , 1995, American journal of human genetics.

[47]  J. Scott,et al.  Genetic linkage between the antigenic group (Ag) variation and the apolipoprotein B gene: assignment of the Ag locus. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[48]  W S Watkins,et al.  Linkage disequilibrium predicts physical distance in the adenomatous polyposis coli region. , 1994, American journal of human genetics.

[49]  S. Weissman.  Genetic bases for common polygenic diseases. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[50]  Wayne P. Maddison,et al.  Genetic Data Analysis: Methods for Discrete Population Genetic Data , 1991 .

[51]  A. Templeton.  Cladistic approaches to identifying determinants of variability in multifactorial phenotypes and the evolutionary significance of variation in the human genome. , 2007, Ciba Foundation symposium.

[52]  M. Brown,et al.  A receptor-mediated pathway for cholesterol homeostasis. , 1986, Science.

[53]  B S Weir,et al.  Maximum-likelihood estimation of gene location by linkage disequilibrium. , 1994, American journal of human genetics.

[54]  R. Mahley,et al.  Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. , 1988, Science.

[55]  C. Sing,et al.  Apolipoprotein E polymorphism and atherosclerosis. , 1988, Arteriosclerosis.

[56]  C. Shoulders,et al.  DNA POLYMORPHISM ADJACENT TO HUMAN APOPROTEIN A-1 GENE: RELATION TO HYPERTRIGLYCERIDAEMIA , 1983, The Lancet.

[57]  C. Sing,et al.  Cladistic analysis of the apolipoprotein AI‐CIH‐AIV gene cluster using a healthy French Canadian sample. I. Haploid analysis , 1995, Annals of human genetics.

[58]  D E Weeks,et al.  Polygenic disease: methods for mapping complex disease traits. , 1995, Trends in genetics : TIG.

[59]  S. Antonarakis,et al.  RFLP for the human lipoprotein lipase (LPL) gene: HindIII. , 1987, Nucleic acids research.

[60]  L. Kruglyak.  What is significant in whole-genome linkage disequilibrium studies? , 1997, American journal of human genetics.

[61]  R. Mahley,et al.  Human apolipoprotein E. The complete amino acid sequence. , 1982, The Journal of biological chemistry.

[62]  F. Clerget-Darpoux,et al.  Systematic search of susceptibility loci with methods using gametic disequilibrium , 1995, Genetic epidemiology.

[63]  S. Karathanasis.  Apolipoprotein multigene family: tandem organization of human apolipoprotein AI, CIII, and AIV genes. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[64]  C. Sing,et al.  A cladistic analysis of phenotype associations with haplotypes inferred from restriction endonuclease mapping. II. The analysis of natural populations. , 1988, Genetics.

[65]  H. Hobbs,et al.  Human LDL receptor gene: HincII polymorphism detected by gene amplification. , 1988, Nucleic acids research.

[66]  E. Boerwinkle,et al.  DNA sequence diversity in a 9.7-kb region of the human lipoprotein lipase gene , 1998, Nature Genetics.

[67]  K. Ishimura-Oka,et al.  Structure and polymorphic map of human lipoprotein lipase gene. , 1990, Biochimica et biophysica acta.

[68]  Polymorphisms in the apolipoprotein AI-CIII gene complex. , 1986, Molecular biology & medicine.

[69]  H. Hobbs,et al.  The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein. , 1990, Annual review of genetics.

[70]  R. Ferrell,et al.  Genetic studies of human apolipoproteins. V. A novel rapid procedure to screen apolipoprotein E polymorphism. , 1988, Journal of lipid research.

[71]  C. Sing,et al.  The gender-specific apolipoprotein E genotype influence on the distribution of plasma lipids and apolipoproteins in the population of Rochester, Minnesota. II. Regression relationships with concomitants. , 1992, American journal of human genetics.

[72]  R. Frankham.  Introduction to quantitative genetics (4th edn): by Douglas S. Falconer and Trudy F.C. Mackay Longman, 1996. £24.99 pbk (xv and 464 pages) ISBN 0582 24302 5 , 1996 .

[73]  S. Deeb,et al.  Structure of the human lipoprotein lipase gene. , 1989, Biochemistry.

[74]  J. Stephens,et al.  Linkage disequilibrium in admixed populations: applications in gene mapping. , 1994, The Journal of heredity.

[75]  P. Kahn.  Genome Research: Gene Hunters Close In On Elusive Prey , 1996 .

[76]  A. Templeton,et al.  A cladistic analysis of phenotypic associations with haplotypes inferred from restriction endonuclease mapping or DNA sequencing. V. Analysis of case/control sampling designs: Alzheimer's disease and the apoprotein E locus. , 1995, Genetics.

[77]  S. Mann,et al.  Ciba Foundation Symposium , 1997 .

[78]  C. Sing,et al.  A cladistic analysis of phenotypic associations with haplotypes inferred from restriction endonuclease mapping and DNA sequence data. III. Cladogram estimation. , 1992, Genetics.

[79]  L. Jorde.  Linkage disequilibrium as a gene-mapping tool. , 1995, American journal of human genetics.

[80]  R. Cortese,et al.  Molecular cloning of human LDL apolipoprotein B cDNA. Evidence for more than one gene per haploid genome. , 1985, Atherosclerosis.

[81]  R. Lewontin,et al.  On measures of gametic disequilibrium. , 1988, Genetics.

[82]  J. Terwilliger.  A powerful likelihood method for the analysis of linkage disequilibrium between trait loci and one or more polymorphic marker loci. , 1995, American journal of human genetics.

[83]  T. Südhof,et al.  The LDL receptor gene: a mosaic of exons shared with different proteins. , 1985, Science.

[84]  R. Davis,et al.  Fasting decreases apolipoprotein B mRNA editing and the secretion of small molecular weight apoB by rat hepatocytes: evidence that the total amount of apoB secreted is regulated post-transcriptionally. , 1990, Journal of lipid research.

[85]  J. Scott,et al.  RFLP for the human apolipoprotein B gene: V;XbaI. , 1985, Nucleic acids research.

[86]  M. Brown,et al.  Familial hypercholesterolemia: a genetic receptor disease. , 1985, Hospital practice.

[87]  N. Risch,et al.  A comparison of linkage disequilibrium measures for fine-scale mapping. , 1995, Genomics.