Compendium of genome-wide scans of lipid-related phenotypes

The genetic dissection of complex inherited diseases is a major challenge. Despite limited success in finding genes, substantial data based on genome-wide scan strategies is now available for a variety of diseases and related phenotypes. This can perhaps best be appreciated in the field of lipid and lipoprotein levels, where the amount of information generated is becoming overwhelming. We have created a database containing the results from whole-genome scans of lipid-related phenotypes undertaken to date. The usefulness of this database is demonstrated by performing a new autosomal genomic scan on apolipoprotein B (apoB), LDL-apoB, and apoA-I levels, measured in 679 subjects of 243 nuclear families. Linkage was tested using both allele-sharing and variance-component methods. Only two loci provided support for linkage with both methods: a LDL-apoB locus on 18q21.32 and an apoA-I locus on 3p25.2.Adding those findings to the database highlighted the fact that the former is reported as a lipid-related locus for the first time, whereas the latter has been observed before. However, concerns arise when displaying all data on the same map, because a large portion of the genome is now covered with loci supported by at least suggestive evidence of linkage. The genetic dissection of complex inherited diseases is a major challenge. Despite limited success in finding genes, substantial data based on genome-wide scan strategies is now available for a variety of diseases and related phenotypes. This can perhaps best be appreciated in the field of lipid and lipoprotein levels, where the amount of information generated is becoming overwhelming. We have created a database containing the results from whole-genome scans of lipid-related phenotypes undertaken to date. The usefulness of this database is demonstrated by performing a new autosomal genomic scan on apolipoprotein B (apoB), LDL-apoB, and apoA-I levels, measured in 679 subjects of 243 nuclear families. Linkage was tested using both allele-sharing and variance-component methods. Only two loci provided support for linkage with both methods: a LDL-apoB locus on 18q21.32 and an apoA-I locus on 3p25.2. Adding those findings to the database highlighted the fact that the former is reported as a lipid-related locus for the first time, whereas the latter has been observed before. However, concerns arise when displaying all data on the same map, because a large portion of the genome is now covered with loci supported by at least suggestive evidence of linkage. Mapping genes involved in complex human diseases is one of the major challenges in human genetics. With the increasing incidence of chronic diseases in industrialized societies, finding these genes is clinically and economically relevant. During the past few years, considerable research resources have been deployed to study the genetic causes of complex human diseases to better understand their pathogenesis and, ultimately, improve prevention strategies, diagnostic tools, and therapies (1Risch N.J. Searching for genetic determinants in the new millennium.Nature. 2000; 405: 847-856Crossref PubMed Scopus (1553) Google Scholar). Encouraged by the early success in the identification of genes responsible for monogenic diseases, many investigators have embraced genome-scan strategies. This trend has resulted in an enormous amount of information, which is now typically difficult to synthesize and interpret for a given complex disease. The importance ascribed to lipid and lipoprotein levels in risk estimation and in the treatment of coronary heart disease (CHD) (2ATP.Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III).J. Am. Med. Assoc. 2001; 285: 2486-2497Crossref Scopus (24129) Google Scholar) has stimulated molecular studies to investigate the genetic causes underlying human variation in these traits. A large number of genome-wide screens of serum lipid-related phenotypes have been performed to date, and a review of such studies seems timely. Because linkage results must be replicated to be credible (3Province M.A. Sequential methods of analysis for genome scans.Adv. Genet. 2001; 42: 499-514Crossref PubMed Google Scholar), a compendium of published quantitative trait loci (QTLs) may facilitate the identification of replicated findings. To provide an example on how such information can be useful, we add the results of a new genome scan of apolipoprotein B (apoB) and apoA-I levels to this compendium. ApoB and apoA-I levels are good markers of CHD risk (4Walldius G. Jungner I. Holme I. Aastveit A.H. Kolar W. Steiner E. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS Study): a prospective study.Lancet. 2001; 358: 2026-2033Abstract Full Text Full Text PDF PubMed Scopus (1048) Google Scholar, 5Lamarche B. Moorjani S. Lupien P.J. Cantin B. Bernard P.M. Dagenais G.R. Despres J.P. Apolipoprotein A-I and B levels and the risk of ischemic heart disease during a five-year follow-up of men in the Quebec Cardiovascular Study.Circulation. 1996; 94: 273-278Crossref PubMed Scopus (436) Google Scholar). A number of studies have clearly established that genetic factors contribute to interindividual differences in apolipoprotein levels. An elegant study comparing identical and fraternal twins reared together with twins reared apart has shown that a large portion of the variance in apoB and apoA-I levels is attributable to genetic factors, with heritability estimates greater than 50% (6Heller D.A. Faire U. de Pedersen N.L. Dahlen G. McClearn G.E. Genetic and environmental influences on serum lipid levels in twins.N. Engl. J. Med. 1993; 328: 1150-1156Crossref PubMed Scopus (395) Google Scholar). In addition, based on complex segregation analyses, major gene effects have been reported for these two phenotypes (7Hasstedt S.J. Wu L. Williams R.R. Major locus inheritance of apolipoprotein B in Utah pedigrees.Genet. Epidemiol. 1987; 4: 67-76Crossref PubMed Scopus (37) Google Scholar, 8Moll P.P. Michels V.V. Weidman W.H. Kottke B.A. Genetic determination of plasma apolipoprotein AI in a population-based sample.Am. J. Hum. Genet. 1989; 44: 124-139PubMed Google Scholar). Mutations in genes that encode apoB, LDL receptor, and ABCA1 have been implicated in monogenic disorders altering plasma apolipoprotein levels, including familial hypobetalipoproteinemia [Online Mendelian Inheritance in Man (OMIM) 605019], familial hypercholesterolemia (OMIM 143890), and hypoalphalipoproteinemia (OMIM 604091). However, these mutations do not account for the variation in plasma apoB and apoA levels in the general population. In an attempt to identify the responsible genes, a large number of association and linkage studies have been performed with candidate genes. These studies have been difficult to interpret because of conflicting results, lack of replication, and the occurrence of positive findings only in specific subgroups. Perhaps the highest linkage signal for apoB levels was reported in Dutch pedigrees on chromosome 1p31 [logarithm of the odds (LOD) = 4.7] (9Allayee H. Krass K.L. Pajukanta P. Cantor R.M. van der Kallen C.J. Mar R. Rotter J.I. de Bruin T.W. Peltonen L. Lusis A.J. Locus for elevated apolipoprotein B levels on chromosome 1p31 in families with familial combined hyperlipidemia.Circ. Res. 2002; 90: 926-931Crossref PubMed Scopus (44) Google Scholar). Other suggestive linkages (LOD > 1.7) have been found on chromosome 12q24 for apoA-I (10Klos K.L. Kardia S.L. Ferrell R.E. Turner S.T. Boerwinkle E. Sing C.F. Genome-wide linkage analysis reveals evidence of multiple regions that influence variation in plasma lipid and apolipoprotein levels associated with risk of coronary heart disease.Arterioscler. Thromb. Vasc. Biol. 2001; 21: 971-978Crossref PubMed Scopus (57) Google Scholar) and on 1p, 11q24, 21q21, and Xq23 for apoB (11Pajukanta P. Terwilliger J.D. Perola M. Hiekkalinna T. Nuotio I. Ellonen P. Parkkonen M. Hartiala J. Ylitalo K. Pihlajamaki J. Porkka K. Laakso M. Viikari J. Ehnholm C. Taskinen M.R. Peltonen L. Genomewide scan for familial combined hyperlipidemia genes in Finnish families, suggesting multiple susceptibility loci influencing triglyceride, cholesterol, and apolipoprotein B levels.Am. J. Hum. Genet. 1999; 64: 1453-1463Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar, 12Pajukanta P. Allayee H. Krass K.L. Kuraishy A. Soro A. Lilja H.E. Mar R. Taskinen M.R. Nuotio I. Laakso M. Rotter J.I. De Bruin T.W. Cantor R.M. Lusis A.J. Peltonen L. Combined analysis of genome scans of Dutch and Finnish families reveals a susceptibility locus for high-density lipoprotein cholesterol on chromosome 16q.Am. J. Hum. Genet. 2003; 72: 903-917Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar). However, other genome-wide scans failed to identify QTLs for apoB levels (10Klos K.L. Kardia S.L. Ferrell R.E. Turner S.T. Boerwinkle E. Sing C.F. Genome-wide linkage analysis reveals evidence of multiple regions that influence variation in plasma lipid and apolipoprotein levels associated with risk of coronary heart disease.Arterioscler. Thromb. Vasc. Biol. 2001; 21: 971-978Crossref PubMed Scopus (57) Google Scholar, 13Aouizerat B.E. Allayee H. Cantor R.M. Davis R.C. Lanning C.D. Wen P.Z. Dallinga-Thie G.M. de Bruin T.W. Rotter J.I. Lusis A.J. A genome scan for familial combined hyperlipidemia reveals evidence of linkage with a locus on chromosome 11.Am. J. Hum. Genet. 1999; 65: 397-412Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar). To search for additional loci influencing apoB and apoA-I levels or to replicate previous findings, we performed an autosomal genome scan among 243 nuclear families participating in the Québec Family Study (QFS). Subjects were participants in the QFS, an ongoing project with French-Canadian families investigating the genetics of obesity and its comorbidities (14Bouchard C. Genetic epidemiology, association, and sib-pair linkage: results from the Québec Family Study.in: Bray G.A. Ryan D.H. Molecular and Genetic Aspects of Obesity. Louisiana State University Press, Baton Rouge, LA1996: 470-481Google Scholar). In this study, 679 subjects of 243 nuclear families had apolipoprotein measurements available. This cohort represents a mixture of random sampling and ascertainment through obese (body mass index > 32 kg/m2) probands. Table 1 presents the characteristics of subjects in each of the sex and generation groups. The study was approved by the Laval University Medical Ethics Committee, and all subjects provided written informed consent. All procedures followed were in accordance with institutional guidelines.TABLE 1Characteristics of genome scan participants by gender and generation groupsVariableFathers (n = 132)Mothers (n = 175)Sons (n = 164)Daughters (n = 208)Age (years) 54.1 ± 9.7 50.9 ± 9.2 27.2 ± 10.8 28.8 ± 11.6Body mass index (kg/m2) 29.5 ± 6.3 30.5 ± 8.5 27.4 ± 7.8 28.3 ± 9.4Total apoB (g/l) 1.13 ± 0.22 1.02 ± 0.24 0.89 ± 0.23 0.87 ± 0.20LDL-apoB (g/l) 1.00 ± 0.20 0.90 ± 0.21 0.80 ± 0.21 0.77 ± 0.19ApoA-I (g/l) 1.20 ± 0.17 1.33 ± 0.20 1.19 ± 0.16 1.24 ± 0.17apoB, apolipoprotein B. Values are means ± SD. Open table in a new tab apoB, apolipoprotein B. Values are means ± SD. Blood samples were obtained from an antecubital vein in the morning after a 12 h overnight fast. The apolipoprotein measurements were performed with the rocket immunoelectrophoretic method (15Laurell C.B. Quantitative estimation of proteins by electrophoresis in agarose gel containing antibodies.Anal. Biochem. 1966; 15: 45-52Crossref PubMed Scopus (3523) Google Scholar). ApoB concentrations were measured in plasma, whereas LDL apoB and apoA-I concentrations were measured in the infranatant (d > 1.006 g/ml) obtained after separation of very low density lipoprotein from the plasma by ultracentrifugation. The measurements were calibrated with reference standards obtained from the Centers for Disease Control and Prevention (Atlanta, GA). A total of 443 markers spanning the 22 autosomal chromosomes with an average intermarker distance of 7.2 centimorgan (cM) were genotyped as described by Chagnon et al. (16Chagnon Y.C. Borecki I.B. Perusse L. Roy S. Lacaille M. Chagnon M. Ho-Kim M.A. Rice T. Province M.A. Rao D.C. Bouchard C. Genome-wide search for genes related to the fat-free body mass in the Quebec Family Study.Metabolism. 2000; 49: 203-207Abstract Full Text PDF PubMed Scopus (104) Google Scholar). The apolipoprotein traits were adjusted for the effects of age (up to cubic polynomial to allow for nonlinearity), gender, and body mass index using a stepwise multiple regression procedure retaining only significant covariates (P < 0.05) as described previously (17Bosse Y. Perusse L. Despres J.P. Lamarche B. Chagnon Y.C. Rice T. Rao D.C. Bouchard C. Vohl M.C. Evidence for a major quantitative trait locus on chromosome 17q21 affecting low-density lipoprotein peak particle diameter.Circulation. 2003; 107: 2361-2368Crossref PubMed Scopus (38) Google Scholar). Adjustments of the phenotypes were performed using SAS (version 8.2). We conducted quantitative trait linkage analyses using both allele-sharing and variance-component methods. For the allele-sharing method, we used the new Haseman-Elston regression-based method (18Elston R.C. Buxbaum S. Jacobs K.B. Olson J.M. Haseman and Elston revisited.Genet. Epidemiol. 2000; 19: 1-17Crossref PubMed Scopus (235) Google Scholar), which models the mean corrected cross-product of the sibs' trait values instead of the squared sib pair trait difference used in the original method (19Haseman J.K. Elston R.C. The investigation of linkage between a quantitative trait and a marker locus.Behav. Genet. 1972; 2: 3-19Crossref PubMed Scopus (1023) Google Scholar). Two-point and multipoint (at 1 cM intervals) estimates of alleles shared identical by descent (IBD) were generated using GENIBD software, and linkage was tested using SIBPAL2 software from the S.A.G.E. 4.0 statistical package (20S.A.G.E. 1999. Statistical Analysis for Genetic Epidemiology, release 4.0. Department of Epidemiology and Biostatistics, Rammelkamp Center for Education and Research, Metro Health Campus, Case Western Reserve University, Cleveland, OH.Google Scholar). The maximum number of sib pairs was 347. Empirical P values of the test statistic were also computed using a Monte Carlo permutation procedure with 10,000 replicate permutations for genomic regions containing two-point linkage markers with suggestive evidence of linkage (P < 0.0023). Linkage was also performed with a variance-component model using the QTDT (quantitative transmission disequilibrium test) computer program (21Abecasis G.R. Cardon L.R. Cookson W.O. A general test of association for quantitative traits in nuclear families.Am. J. Hum. Genet. 2000; 66: 279-292Abstract Full Text Full Text PDF PubMed Scopus (959) Google Scholar). Under this model, a phenotype is influenced by the additive effects of a QTL (q), a residual familial component attributable to polygenes (g), and a residual nonfamilial component (e). Hypothesis testing was performed with the likelihood ratio test. The likelihood of the null hypothesis is obtained by restricting the additive genetic variance attributable to the QTL (σq) equal to zero (σq = 0). The test is conducted by contrasting this restricted model with the alternative, in which σq is estimated (σq ≠ 0). The difference in minus twice the log likelihoods between the null and alternative hypotheses is approximately distributed as a Chi-square, which allowed LOD score computation as χ2/(2 loge 10). We have taken a LOD score of ⩾3.00 (P ⩽ 0.0001) as evidence of linkage and a LOD score of ⩾1.75 (P ⩽ 0.0023) as evidence of suggestive linkage (22Rao D.C. Province M.A. The future of path analysis, segregation analysis, and combined models for genetic dissection of complex traits.Hum. Hered. 2000; 50: 34-42Crossref PubMed Scopus (58) Google Scholar). We have also retained LOD scores of ⩾1.18 (P ⩽ 0.01) to identify potential independent confirmation of a previously reported significant linkage (23Lander E. Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results.Nat. Genet. 1995; 11: 241-247Crossref PubMed Scopus (4464) Google Scholar). The initial search for genome-wide scan publications on lipid-related phenotypes was accomplished with keywords (genome scan + lipoprotein and linkage + lipoprotein + genome) at the bioinformatics site of the National Center for Biotechnology Information (www.ncbi.nlm.nih.gov). The publication list was completed and verified by examination of both the discussion section and the reference list of the publication found in the initial search. The search focused on results published before the end of April 2003 and excluded abstracts presented at meetings. A whole-genome scan Excel database for lipid-related phenotypes was established. The database contained bibliographic details (first author, source, and years), study population (ethnicity), ascertainment scheme, phenotypic traits, sample size details (number of individuals, sib pairs, and families), linkage analysis methods, and results. Any evidence of linkage, from suggestive and better (LOD score ⩾ 1.7 or P ⩽ 0.0023) was treated as an observation (a hit). Results were entered in the database with the name of the linked marker/gene, its location (megabase and chromosomal band), and its maximum LOD score or Z score or P value. For most studies, markers were provided in the papers and were those defining the peak or were the closest to the signal. When the marker's name or the specific location of the QTL (hits) was not available in the original paper, the authors were contacted and asked to provide the missing information. To identify possible replication and compared loci across studies, the location of each linked marker/gene was positioned on a single map provided by the Human Genome browser of the University of California, Santa Cruz (assembly, June 2002; http://genome.ucsc.edu). When a two-stage strategy was reported in the publication, the P value of the second stage was favored unless it did not reach the criteria to be included in Table 4 (criteria based on whole-genome scan). This decision was made to take the best out of these studies considering that the criteria for claiming significant linkage are different between the first and second stages of the analysis. Similarly, when multiple linkage methods were used in the same publication, the most significant result was kept for the database.TABLE 4Evidence for the presence of linkage with lipid-related phenotypes from genome-wide scan studies: status as April 2003Markers or GenesLocationaThe physical and genetic locations of markers and genes are from the Genome Browser of the University of California, Santa Cruz (http://genome.ucsc.edu).Chromosome BandaThe physical and genetic locations of markers and genes are from the Genome Browser of the University of California, Santa Cruz (http://genome.ucsc.edu).SamplesPhenotypesP, Z, or LOD ValuesReferencesMbD1S1608, 37354.3–65.11p36.32-p31.331 subjects; 1 kindredFHLOD = 6.858Hunt S.C. Hopkins P.N. Bulka K. McDermott M.T. Thorne T.L. Wardell B.B. Bowen B.R. Ballinger D.G. Skolnick M.H. Samuels M.E. Genetic localization to chromosome 1p32 of the third locus for familial hypercholesterolemia in a Utah kindred.Arterioscler. Thromb. Vasc. Biol. 2000; 20: 1089-1093Crossref PubMed Scopus (90) Google ScholarD1S214, 2286.5–13.41p36.31-p36.21576 subjects; 42 familiesLDL-CLOD = 2.445Elbein S.C. Hasstedt S.J. Quantitative trait linkage analysis of lipid-related traits in familial type 2 diabetes: evidence for linkage of triglyceride levels to chromosome 19q.Diabetes. 2002; 51: 528-535Crossref PubMed Scopus (75) Google ScholarD1S2826, 51318.1–31.11p36.13-p35.274 subjects; 1 kindredFHLOD = 3.144Al-Kateb H. Bahring S. Hoffmann K. Strauch K. Busjahn A. Nurnberg G. Jouma M. Bautz E.K. Dresel H.A. Luft F.C. Mutation in the ARH gene and a chromosome 13q locus influence cholesterol levels in a new form of digenic-recessive familial hypercholesterolemia.Circ. Res. 2002; 90: 951-958Crossref PubMed Scopus (47) Google ScholarD1S552, 284318.8–20.11p36.13-p36.12Twins and parentsCholesterolLOD = 1.844Al-Kateb H. Bahring S. Hoffmann K. Strauch K. Busjahn A. Nurnberg G. Jouma M. Bautz E.K. Dresel H.A. Luft F.C. Mutation in the ARH gene and a chromosome 13q locus influence cholesterol levels in a new form of digenic-recessive familial hypercholesterolemia.Circ. Res. 2002; 90: 951-958Crossref PubMed Scopus (47) Google ScholarLDL-CLOD = 1.944Al-Kateb H. Bahring S. Hoffmann K. Strauch K. Busjahn A. Nurnberg G. Jouma M. Bautz E.K. Dresel H.A. Luft F.C. Mutation in the ARH gene and a chromosome 13q locus influence cholesterol levels in a new form of digenic-recessive familial hypercholesterolemia.Circ. Res. 2002; 90: 951-958Crossref PubMed Scopus (47) Google ScholarD1S2725, 278721.7–27.31p36.12-p35.317 subjects; 2 familiesFHLOD = 5.360Eden E.R. Naoumova R.P. Burden J.J. McCarthy M.I. Soutar A.K. Use of homozygosity mapping to identify a region on chromosome 1 bearing a defective gene that causes autosomal recessive homozygous hypercholesterolemia in two unrelated families.Am. J. Hum. Genet. 2001; 68: 653-660Abstract Full Text Full Text PDF PubMed Scopus (49) Google ScholarD1S233, 19331.3–431p35.2-q34.2576 subjects; 42 familiesRatio LDL/HDLLOD = 2.145Elbein S.C. Hasstedt S.J. Quantitative trait linkage analysis of lipid-related traits in familial type 2 diabetes: evidence for linkage of triglyceride levels to chromosome 19q.Diabetes. 2002; 51: 528-535Crossref PubMed Scopus (75) Google ScholarD1S2892, 272240.2–41.61p34.21 pedigree; 12 familiesFHLOD = 3.161Varret M. Rabes J.P. Saint-Jore B. Cenarro A. Marinoni J.C. Civeira F. Devillers M. Krempf M. Coulon M. Thiart R. Kotze M.J. Schmidt H. Buzzi J.C. Kostner G.M. Bertolini S. Pocovi M. Rosa A. Farnier M. Martinez M. Junien C. Boileau C. A third major locus for autosomal dominant hypercholesterolemia maps to 1p34.1-p32.Am. J. Hum. Genet. 1999; 64: 1378-1387Abstract Full Text Full Text PDF PubMed Scopus (145) Google ScholarD1S40558.71p32.1383 sib pairs; 75 familiesTGZ = 3.140Reed D.R. Nanthakumar E. North M. Bell C. Price R.A. A genome-wide scan suggests a locus on chromosome 1q21-q23 contributes to normal variation in plasma cholesterol concentration.J. Mol. Med. 2001; 79: 262-269Crossref PubMed Scopus (30) Google ScholarLEPR65.91p31.2681 subjects; 236 nuclear familiesLDL-PPDLOD = 2.617Bosse Y. Perusse L. Despres J.P. Lamarche B. Chagnon Y.C. Rice T. Rao D.C. Bouchard C. Vohl M.C. Evidence for a major quantitative trait locus on chromosome 17q21 affecting low-density lipoprotein peak particle diameter.Circulation. 2003; 107: 2361-2368Crossref PubMed Scopus (38) Google ScholarD1S166574.41p31.1269 subjects; 48 familiesApoB (qualitative)LOD = 2.012Pajukanta P. Allayee H. Krass K.L. Kuraishy A. Soro A. Lilja H.E. Mar R. Taskinen M.R. Nuotio I. Laakso M. Rotter J.I. De Bruin T.W. Cantor R.M. Lusis A.J. Peltonen L. Combined analysis of genome scans of Dutch and Finnish families reveals a susceptibility locus for high-density lipoprotein cholesterol on chromosome 16q.Am. J. Hum. Genet. 2003; 72: 903-917Abstract Full Text Full Text PDF PubMed Scopus (80) Google ScholarD1S484158.61q23.3383 sib pairs; 75 familiesCholesterolZ = 3.440Reed D.R. Nanthakumar E. North M. Bell C. Price R.A. A genome-wide scan suggests a locus on chromosome 1q21-q23 contributes to normal variation in plasma cholesterol concentration.J. Mol. Med. 2001; 79: 262-269Crossref PubMed Scopus (30) Google ScholarD1S16791601q23.31,406 subjects; 513 familiesLp[a]LOD = 3.849Broeckel U. Hengstenberg C. Mayer B. Holmer S. Martin L.J. Comuzzie A.G. Blangero J. Nurnberg P. Reis A. Riegger G.A. Jacob H.J. Schunkert H. A comprehensive linkage analysis for myocardial infarction and its related risk factors.Nat. Genet. 2002; 30: 210-214Crossref PubMed Scopus (282) Google ScholarD1S104161.31q23.3269 subjects; 48 familiesTG (qualitative)LOD = 2.812Pajukanta P. Allayee H. Krass K.L. Kuraishy A. Soro A. Lilja H.E. Mar R. Taskinen M.R. Nuotio I. Laakso M. Rotter J.I. De Bruin T.W. Cantor R.M. Lusis A.J. Peltonen L. Combined analysis of genome scans of Dutch and Finnish families reveals a susceptibility locus for high-density lipoprotein cholesterol on chromosome 16q.Am. J. Hum. Genet. 2003; 72: 903-917Abstract Full Text Full Text PDF PubMed Scopus (80) Google ScholarFCHLLOD = 2.512Pajukanta P. Allayee H. Krass K.L. Kuraishy A. Soro A. Lilja H.E. Mar R. Taskinen M.R. Nuotio I. Laakso M. Rotter J.I. De Bruin T.W. Cantor R.M. Lusis A.J. Peltonen L. Combined analysis of genome scans of Dutch and Finnish families reveals a susceptibility locus for high-density lipoprotein cholesterol on chromosome 16q.Am. J. Hum. Genet. 2003; 72: 903-917Abstract Full Text Full Text PDF PubMed Scopus (80) Google ScholarD1S2623bWhen the authors provided only the location of linkage (in genetic distance) without mentioning the name of the marker, we identified a possible marker within the region showing evidence of linkage from the genetic map used by the authors.180.41q25.3649 sib pairsHDL-CLOD = 2.141Coon H. Leppert M.F. Eckfeldt J.H. Oberman A. Myers R.H. Peacock J.M. Province M.A. Hopkins P.N. Heiss G. Genome-wide linkage analysis of lipids in the Hypertension Genetic Epidemiology Network (HyperGEN) Blood Pressure Study.Arterioscler. Thromb. Vasc. Biol. 2001; 21: 1969-1976Crossref PubMed Scopus (66) Google ScholarD1S547239.81q43930 subjects; 292 nuclear familiesLDL-CLOD = 2.546Bosse Y. Chagnon Y.C. Despres J.P. Rice T. Rao D.C. Bouchard C. Perusse L. Vohl M.C. Genome-wide linkage scan reveals multiple susceptibility loci influencing lipid and lipoprotein levels in the Quebec Family Study.J. Lipid Res. 2004; 45: 419-426Abstract Full Text Full Text PDF PubMed Scopus (62) Google ScholarD2S2211bWhen the authors provided only the location of linkage (in genetic distance) without mentioning the name of the marker, we identified a possible marker within the region showing evidence of linkage from the genetic map used by the authors.7.32p25.1649 sib pairsCholesterolLOD = 2.241Coon H. Leppert M.F. Eckfeldt J.H. Oberman A. Myers R.H. Peacock J.M. Province M.A. Hopkins P.N. Heiss G. Genome-wide linkage analysis of lipids in the Hypertension Genetic Epidemiology Network (HyperGEN) Blood Pressure Study.Arterioscler. Thromb. Vasc. Biol. 2001; 21: 1969-1976Crossref PubMed Scopus (66) Google ScholarD2S29527.92p25.1269 subjects; 48 familiesApoB (qualitative)LOD = 1.812Pajukanta P. Allayee H. Krass K.L. Kuraishy A. Soro A. Lilja H.E. Mar R. Taskinen M.R. Nuotio I. Laakso M. Rotter J.I. De Bruin T.W. Cantor R.M. Lusis A.J. Peltonen L. Combined analysis of genome scans of Dutch and Finnish families reveals a susceptibility locus for high-density lipoprotein cholesterol on chromosome 16q.Am. J. Hum. Genet. 2003; 72: 903-917Abstract Full Text Full Text PDF PubMed Scopus (80) Google ScholarTG (qualitative)LOD = 1.812Pajukanta P. Allayee H. Krass K.L. Kuraishy A. Soro A. Lilja H.E. Mar R. Taskinen M.R. Nuotio I. Laakso M. Rotter J.I. De Bruin T.W. Cantor R.M. Lusis A.J. Peltonen L. Combined analysis of genome scans of Dutch and Finnish families reveals a susceptibility locus for high-density lipoprotein cholesterol on chromosome 16q.Am. J. Hum. Genet. 2003; 72: 903-917Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar240 subjects; 18 familiesFCHLLOD = 2.613Aouizerat B.E. Allayee H. Cantor R.M. Davis R.C. Lanning C.D. Wen P.Z. Dallinga-Thie G.M. de Bruin T.W. Rotter J.I. Lusis A.J. A genome scan for familial combined hyperlipidemia reveals evidence of linkage with a locus on chromosome 11.Am. J. Hum. Genet. 1999; 65: 397-412Abstract Full Text Full Text PDF PubMed Scopus (109) Google ScholarD2S4239.72p25.1269 subjects; 48 familiesFCHLLOD = 2.212Pajukanta P. Allayee H. Krass K.L. Kuraishy A. Soro A. Lilja H.E. Mar R. Taskinen M.R. Nuotio I. Laakso M. Rotter J.I. De Bruin T.W. Cantor R.M. Lusis A.J. Peltonen L. Combined analysis of genome scans of Dutch and Finnish families reveals a susceptibility locus for high-density lipoprotein cholesterol on chromosome 16q.Am. J. Hum. Genet. 2003; 72: 903-917Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar29 familiesHDL-C (qualitative)LOD = 3.426Soro A. Pajukanta P. Lilja H.E. Ylitalo K. Hiekkalinna T. Perola M. Cantor R.M. Viikari J.S. Taskinen M.R. Peltonen L. Genome scans provide evidence for low-HDL-C loci on chromosomes 8q23, 16q24.1-24.2, and 20q13.11 in Finnish families.Am. J. Hum. 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Viikari J.S. Taskinen M.R. Peltonen L. Genome scans provide evidence for low-HDL-C loci on