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Meta-Analysis of Genome-Wide Studies of Psoriasis Susceptibility Reveals Linkage to Chromosomes 6p21 and 4q28–q31 in Caucasian and Chinese Hans Population

2004; Elsevier BV; Volume: 122; Issue: 6 Linguagem: Inglês

10.1111/j.0022-202x.2004.22607.x

ISSN

1523-1747

Autores

Gurdeep S. Sagoo, Rachid Tazi‐Ahnini, Juliet N. Barker, James T. Elder, Rajan P. Nair, Lena Samuelsson, Heiko Traupe, Richard C. Trembath, Darren Robinson, Mark M. Iles,

Tópico(s)

Dermatology and Skin Diseases

Resumo

Ten genome-wide scans have been conducted over the past few years in the search for psoriasis susceptibility genes, but only one potential susceptibility region has been consistently replicated. A meta-analysis using the genome-search meta-analysis method was undertaken combining the results of six of these psoriasis genome-wide studies. The results of this analysis revealed linkage to the major histocompatibility complex on chromosome 6p21 that includes the PSORS1 locus. In addition, linkage was also recorded to a region on chromosome 4q28–q31 previously identified only in a Chinese Hans population. Both these regions were statistically significant even after correction for multiple testing. A possible reason for the erratic replication of findings could be the large effect of the PSORS1 locus (6p21) masking the effect of other loci involved in psoriasis. To overcome this problem, we suggest that future studies condition on the effect of the PSORS1 locus. Ten genome-wide scans have been conducted over the past few years in the search for psoriasis susceptibility genes, but only one potential susceptibility region has been consistently replicated. A meta-analysis using the genome-search meta-analysis method was undertaken combining the results of six of these psoriasis genome-wide studies. The results of this analysis revealed linkage to the major histocompatibility complex on chromosome 6p21 that includes the PSORS1 locus. In addition, linkage was also recorded to a region on chromosome 4q28–q31 previously identified only in a Chinese Hans population. Both these regions were statistically significant even after correction for multiple testing. A possible reason for the erratic replication of findings could be the large effect of the PSORS1 locus (6p21) masking the effect of other loci involved in psoriasis. To overcome this problem, we suggest that future studies condition on the effect of the PSORS1 locus. genome search meta-analysis major histocompatibility Psoriasis is a chronic inflammatory dermatosis affecting approximately 2%–5% of the Caucasian population (Nevitt and Hutchinson, 1996Nevitt G.J. Hutchinson P.E. Psoriasis in the community: Prevalence, severity and patients' beliefs and attitudes towards the disease.Br J Dermatol. 1996; 135: 533-537Crossref PubMed Scopus (233) Google Scholar) and 0.1%–0.3% in the Far East (Simons, 1949Simons R.D. Additional studies on psoriasis in the tropics and in the starvation camps.Am Acad Dermatol. 1949; 11: 937-947Google Scholar) and China (Yui Yip, 1984Yui Yip S. The prevalence of psoriasis in the mongoloid race.J Am Acad Dermatol. 1984; 10: 965-968Abstract Full Text PDF PubMed Scopus (126) Google Scholar). Familial studies have suggested a multifactorial mode of inheritance, and the view that psoriasis is a disease involving gene–gene and gene–environment interactions is widely held (Elder et al., 2001Elder J.T. Nair R.P. Henseler T. et al.The genetics of psoriasis 2001 the odyssey continues.Arch Dermatol. 2001; 137: 1447-1454Crossref PubMed Google Scholar). The genes involved in psoriasis are believed to interact with several environmental triggers including streptococcal infection, stress, smoking, and physical trauma (Swanbeck et al., 1994Swanbeck G. Inerot A. Martinsson T. Wahlström J. A population genetic study of psoriasis.Br J Dermatol. 1994; 131: 32-39Crossref PubMed Scopus (101) Google Scholar; Tagami, 1997Tagami H. Triggering factors.Clin Dermatol. 1997; 15: 677-685Abstract Full Text PDF PubMed Scopus (51) Google Scholar). Several genome-wide scans have been conducted over the last few years in the search for genes predisposing to familial psoriasis (Tomfohrde et al., 1994Tomfohrde J. Silverman A. Barnes R. et al.Gene for familial psoriasis susceptibility mapped to the distal end of human chromosome 17q.Science. 1994; 264: 1141-1145Crossref PubMed Scopus (380) Google Scholar; Matthews et al., 1996Matthews D. Fry L. Powles A. et al.Evidence that a locus for familial psoriasis maps to chromosome 4q.Nat Genet. 1996; 14: 231-233Crossref PubMed Scopus (188) Google Scholar; Nair et al., 1997Nair R.P. Henseler T. Jenisch S. et al.Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan.Hum Mol Genet. 1997; 6: 1349-1356Crossref PubMed Scopus (373) Google Scholar; Trembath et al., 1997Trembath R.C. Clough R.L. Rosbotham J.L. et al.Identification of a major susceptibility locus on chromosome 6p and evidence for further disease loci revealed by a two stage genome-wide search in psoriasis.Hum Mol Genet. 1997; 6: 813-820Crossref PubMed Scopus (460) Google Scholar; Capon et al., 1999Capon F. Novelli G. Semprini S. et al.Searching for psoriasis susceptibility genes in Italy: Genome scan and evidence for a new locus on chromosome 1.J Invest Dermatol. 1999; 112: 32-35Crossref PubMed Scopus (167) Google Scholar; Samuelsson et al., 1999Samuelsson L. Enlund F. Torinsson A. et al.A genome-wide search for genes predisposing to familial psoriasis by using a stratification approach.Hum Genet. 1999; 105: 523-529Crossref PubMed Scopus (105) Google Scholar; Lee et al., 2000Lee Y.-A. Ruschendorf F. Windemuth C. et al.Genome wide scan in German families reveals evidence for a novel psoriasis-susceptibility locus on chromosome 19p13.Am J Hum Genet. 2000; 67: 1020-1024Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar; Veal et al., 2001Veal C.D. Clough R.L. Barber R.C. et al.Identification of a novel psoriasis susceptibility locus at 1p and evidence of epistasis between PSORS1 and candidate loci.J Med Genet. 2001; 38: 7-13Crossref PubMed Scopus (124) Google Scholar; Zhang et al., 2002Zhang X.J. He P.P. Wang Z.X. et al.Evidence for a major psoriasis susceptibility locus at 6p21 (PSORS1) and a novel candidate region at 4q31 by genome-wide scan in Chinese Hans.J Invest Dermatol. 2002; 119: 1361-1366Crossref PubMed Scopus (98) Google Scholar; Asumalahti et al., 2003Asumalahti K. Latitinen T. Lahermo P. et al.Psoriasis susceptibility locus on 18p revealed by genome scan in Finnish families not associated with PSORS1.J Invest Dermatol. 2003; 121: 735-740Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). These studies have confirmed previous findings and also indicated novel candidate regions. Eight loci designated PSORS1-7 and PSORS9 with a further 11 undesignated loci have been identified as potential psoriasis susceptibility loci Table I. These 19 loci are located on 15 different chromosomes and of these regions only the locus on the short arm of chromosome 6 within the major histocompatibility complex (MHC) is consistently implicated in psoriasis (see Table I). Of the other regions, only three on chromosomes 17q25, 19p13, and 20p have been implicated by more than one genome-wide study. Several regions have been replicated in other studies focussing on specific regions. For instance, chromosomes 1q, 2p, 4q13, and 14q have been implicated by Bhalerao and Bowcock, 1998Bhalerao J. Bowcock A.M. The genetics of psoriasis: A complex disorder of the skin and immune system.Hum Mol Genet. 1998; 7: 1537-1545Crossref PubMed Scopus (237) Google Scholar, chromosome 3q by Enlund et al., 1999aEnlund F. Samuelsson L. Enerback C. et al.Psoriasis susceptibility locus in chromosome region 3q21 identified in patients from southwest Sweden.Eur J Hum Genet. 1999; 7: 783-790Crossref PubMed Scopus (119) Google Scholar, and chromosome 17q25 by Enlund et al., 1999bEnlund F. Samuelsson L. Enerback C. et al.Analysis of three suggested psoriasis susceptibility loci in a large Swedish set of families: Confirmation of linkage to chromosome 6p (HLA region), and to 17q, but not to 4q.Hum Hered. 1999; 49: 2-8Crossref PubMed Scopus (74) Google Scholar. Thus, although these genome-wide scans have proved to be useful in identifying genetic regions that may potentially harbor disease susceptibility genes, replication of significant results and a systematic method of reviewing these results has not been forthcoming.Table IList of published putative psoriasis susceptibility loci from genome-wide studies(updated and adapted from Capon et al., 2002Capon F. Munro M. Barker J. Trembath R. Searching for the major histocompatibility complex psoriasis susceptibility gene.J Invest Dermatol. 2002; 118: 745-751Crossref PubMed Scopus (140) Google Scholar)LocationLocus name (if applicable)Linkage reports1pPSORS7Veal et al., 2001Veal C.D. Clough R.L. Barber R.C. et al.Identification of a novel psoriasis susceptibility locus at 1p and evidence of epistasis between PSORS1 and candidate loci.J Med Genet. 2001; 38: 7-13Crossref PubMed Scopus (124) Google Scholar1qPSORS4Capon et al., 1999Capon F. Novelli G. Semprini S. et al.Searching for psoriasis susceptibility genes in Italy: Genome scan and evidence for a new locus on chromosome 1.J Invest Dermatol. 1999; 112: 32-35Crossref PubMed Scopus (167) Google Scholar2pVeal et al., 2001Veal C.D. Clough R.L. Barber R.C. et al.Identification of a novel psoriasis susceptibility locus at 1p and evidence of epistasis between PSORS1 and candidate loci.J Med Genet. 2001; 38: 7-13Crossref PubMed Scopus (124) Google Scholar2qTrembath et al., 1997Trembath R.C. Clough R.L. Rosbotham J.L. et al.Identification of a major susceptibility locus on chromosome 6p and evidence for further disease loci revealed by a two stage genome-wide search in psoriasis.Hum Mol Genet. 1997; 6: 813-820Crossref PubMed Scopus (460) Google Scholar3qPSORS5Samuelsson et al., 1999Samuelsson L. Enlund F. Torinsson A. et al.A genome-wide search for genes predisposing to familial psoriasis by using a stratification approach.Hum Genet. 1999; 105: 523-529Crossref PubMed Scopus (105) Google Scholar4q13Samuelsson et al., 1999Samuelsson L. Enlund F. Torinsson A. et al.A genome-wide search for genes predisposing to familial psoriasis by using a stratification approach.Hum Genet. 1999; 105: 523-529Crossref PubMed Scopus (105) Google Scholar4q31PSORS9Zhang et al., 2002Zhang X.J. He P.P. Wang Z.X. et al.Evidence for a major psoriasis susceptibility locus at 6p21 (PSORS1) and a novel candidate region at 4q31 by genome-wide scan in Chinese Hans.J Invest Dermatol. 2002; 119: 1361-1366Crossref PubMed Scopus (98) Google Scholar4q34PSORS3Matthews et al., 1996Matthews D. Fry L. Powles A. et al.Evidence that a locus for familial psoriasis maps to chromosome 4q.Nat Genet. 1996; 14: 231-233Crossref PubMed Scopus (188) Google Scholar6p21.3PSORS1Nair et al., 1997Nair R.P. Henseler T. Jenisch S. et al.Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan.Hum Mol Genet. 1997; 6: 1349-1356Crossref PubMed Scopus (373) Google Scholar; Trembath et al., 1997Trembath R.C. Clough R.L. Rosbotham J.L. et al.Identification of a major susceptibility locus on chromosome 6p and evidence for further disease loci revealed by a two stage genome-wide search in psoriasis.Hum Mol Genet. 1997; 6: 813-820Crossref PubMed Scopus (460) Google Scholar; Samuelsson et al., 1999Samuelsson L. Enlund F. Torinsson A. et al.A genome-wide search for genes predisposing to familial psoriasis by using a stratification approach.Hum Genet. 1999; 105: 523-529Crossref PubMed Scopus (105) Google Scholar; Veal et al., 2001Veal C.D. Clough R.L. Barber R.C. et al.Identification of a novel psoriasis susceptibility locus at 1p and evidence of epistasis between PSORS1 and candidate loci.J Med Genet. 2001; 38: 7-13Crossref PubMed Scopus (124) Google Scholar; Zhang et al., 2002Zhang X.J. He P.P. Wang Z.X. et al.Evidence for a major psoriasis susceptibility locus at 6p21 (PSORS1) and a novel candidate region at 4q31 by genome-wide scan in Chinese Hans.J Invest Dermatol. 2002; 119: 1361-1366Crossref PubMed Scopus (98) Google Scholar7Veal et al., 2001Veal C.D. Clough R.L. Barber R.C. et al.Identification of a novel psoriasis susceptibility locus at 1p and evidence of epistasis between PSORS1 and candidate loci.J Med Genet. 2001; 38: 7-13Crossref PubMed Scopus (124) Google Scholar8qTrembath et al., 1997Trembath R.C. Clough R.L. Rosbotham J.L. et al.Identification of a major susceptibility locus on chromosome 6p and evidence for further disease loci revealed by a two stage genome-wide search in psoriasis.Hum Mol Genet. 1997; 6: 813-820Crossref PubMed Scopus (460) Google Scholar9q33Zhang et al., 2002Zhang X.J. He P.P. Wang Z.X. et al.Evidence for a major psoriasis susceptibility locus at 6p21 (PSORS1) and a novel candidate region at 4q31 by genome-wide scan in Chinese Hans.J Invest Dermatol. 2002; 119: 1361-1366Crossref PubMed Scopus (98) Google Scholar14qVeal et al., 2001Veal C.D. Clough R.L. Barber R.C. et al.Identification of a novel psoriasis susceptibility locus at 1p and evidence of epistasis between PSORS1 and candidate loci.J Med Genet. 2001; 38: 7-13Crossref PubMed Scopus (124) Google Scholar15Samuelsson et al., 1999Samuelsson L. Enlund F. Torinsson A. et al.A genome-wide search for genes predisposing to familial psoriasis by using a stratification approach.Hum Genet. 1999; 105: 523-529Crossref PubMed Scopus (105) Google Scholar16qNair et al., 1997Nair R.P. Henseler T. Jenisch S. et al.Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan.Hum Mol Genet. 1997; 6: 1349-1356Crossref PubMed Scopus (373) Google Scholar17q25PSORS2Tomfohrde et al., 1994Tomfohrde J. Silverman A. Barnes R. et al.Gene for familial psoriasis susceptibility mapped to the distal end of human chromosome 17q.Science. 1994; 264: 1141-1145Crossref PubMed Scopus (380) Google Scholar; Nair et al., 1997Nair R.P. Henseler T. Jenisch S. et al.Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan.Hum Mol Genet. 1997; 6: 1349-1356Crossref PubMed Scopus (373) Google Scholar; Samuelsson et al., 1999Samuelsson L. Enlund F. Torinsson A. et al.A genome-wide search for genes predisposing to familial psoriasis by using a stratification approach.Hum Genet. 1999; 105: 523-529Crossref PubMed Scopus (105) Google Scholar18p11Asumalahti et al., 2003Asumalahti K. Latitinen T. Lahermo P. et al.Psoriasis susceptibility locus on 18p revealed by genome scan in Finnish families not associated with PSORS1.J Invest Dermatol. 2003; 121: 735-740Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar19p13PSORS6Lee et al., 2000Lee Y.-A. Ruschendorf F. Windemuth C. et al.Genome wide scan in German families reveals evidence for a novel psoriasis-susceptibility locus on chromosome 19p13.Am J Hum Genet. 2000; 67: 1020-1024Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar; Veal et al., 2001Veal C.D. Clough R.L. Barber R.C. et al.Identification of a novel psoriasis susceptibility locus at 1p and evidence of epistasis between PSORS1 and candidate loci.J Med Genet. 2001; 38: 7-13Crossref PubMed Scopus (124) Google Scholar20pNair et al., 1997Nair R.P. Henseler T. Jenisch S. et al.Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan.Hum Mol Genet. 1997; 6: 1349-1356Crossref PubMed Scopus (373) Google Scholar; Trembath et al., 1997Trembath R.C. Clough R.L. Rosbotham J.L. et al.Identification of a major susceptibility locus on chromosome 6p and evidence for further disease loci revealed by a two stage genome-wide search in psoriasis.Hum Mol Genet. 1997; 6: 813-820Crossref PubMed Scopus (460) Google Scholar Open table in a new tab The best way to combine and analyze the results of the genome-wide studies that have been conducted on familial psoriasis is by conducting a meta-analysis. A meta-analysis is a statistical procedure by which results from individual studies are combined to produce a test of a particular hypothesis. In conducting a meta-analysis, we may confirm previous findings or find novel susceptibility loci where the genetic effect is too small to be detected in any single study.Gu et al., 1998Gu C. Province M. Todorov A. Rao D.C. Meta-analysis methodology for combining non-parametric sib pair linkage results: Genetic homogeneity and identical markers.Genetic Epidemiol. 1998; 15: 609-626Crossref PubMed Scopus (41) Google Scholar developed a meta-analysis of genome-wide studies that pools the results of sib-pair studies. The major drawback of this method is that the same markers must be used in each study and this is rarely the case.Wise et al., 1999Wise L.H. Lanchbury J.S. Lewis C.M. Meta-analysis of genome searches.Ann Hum Genet. 1999; 63: 263-272Crossref PubMed Google Scholar have developed a more generally applicable genome search meta-analysis (GSMA) method utilizing published results from genome-wide studies to identify genetic regions that show evidence of linkage across studies. The GSMA method has been designed to be robust across study designs, and does not require the use of a common set of markers across the studies. Only the marker positions and their p-values or LOD scores are required for this analysis. It is for these reasons that we felt the GSMA method was ideally suited to analyzing the psoriasis genome screens. The results of the meta-analysis carried out on the six genome-wide studies for which results were available can be seen in Fig 1, with the highest-ranking bins (p<0.05) listed in Table II. A total of five bins lay above the 95% threshold, with three of these being above the 99% threshold. After correction for multiple testing (either by the Bonferroni method or by a permutation method), only the two highest of these were significant. The highest-ranking bin (position 33—66 cM on chromosome 6) corresponds to the PSORS1 susceptibility locus within the MHC reported by 6 of the studies (p=3.37×10−6 after correction). The bin adjacent to this (position 66–99 cM on chromosome 6) was ranked third (p=0.40 after correction). The second highest ranked bin (position 132–165 cM on chromosome 4) corresponds to a novel candidate region previously reported only by Zhang et al., 2002Zhang X.J. He P.P. Wang Z.X. et al.Evidence for a major psoriasis susceptibility locus at 6p21 (PSORS1) and a novel candidate region at 4q31 by genome-wide scan in Chinese Hans.J Invest Dermatol. 2002; 119: 1361-1366Crossref PubMed Scopus (98) Google Scholar in the Chinese Hans population (p=0.02 after correction).Table IIBins with p-values <0.05 from our meta-analysis of all six psoriasis genome-wide scans and the five Caucasian psoriasis genome-wide scansAll six studiesCaucasian studies onlyRankChromosomal positionp-valueChromosomal positionp-value16p21 (33–66 cM)3.06×10−8 (<0.00001)6p21 (33–66 cM)9.62×10−7 (<0.00001)24q31 (132–165 cM)2.47×10−4(0.0117)4q31 (132–165 cM)1.69×10−3 (0.13977)36p12–q15 (66–99 cM)4.64×10−3 (0.34987)6p12–q15 (66–99 cM)0.019 (0.86587)413q (66–99 cM)0.038 (0.95632)16q23–q24 (99–end)0.039 (0.9781)516q23–q24 (99–end)0.049 (0.99134)10q26 (165–end)0.044 (0.99013)610q26 (165–end)0.054 (0.99934)17p12–p13 (0–33 cM)0.048 (0.99523)Nominal p-values followed in brackets by p-values estimated by permutation to account for multiple testing. Open table in a new tab Nominal p-values followed in brackets by p-values estimated by permutation to account for multiple testing. When the data were re-analyzed without the Chinese Hans study (2002), six bins were above the 95% threshold Table II, with two above the 99% threshold. The three top-ranking bins were the same as in the previous analysis. Only the highest ranked bin remained significant once multiple testing was accounted for. We tested the robustness of our results to the absence of each of the Caucasian studies by repeating the meta-analysis five times excluding a different Caucasian study each time. In each case, the top three ranked regions remained the same as in the full meta-analysis, except one where the third ranked region dropped to fourth place. A meta-analysis was conducted using data from six previously published genome-wide scans. After correction for multiple testing, two regions on chromosomes 6p21 and 4q31 were found to be significant (p<0.05). The MHC region on chromosome 6p21 was previously reported in all six of the studies used here but the genetic region on chromosome 4q28–q31 was only reported as significant by Zhang et al., 2002Zhang X.J. He P.P. Wang Z.X. et al.Evidence for a major psoriasis susceptibility locus at 6p21 (PSORS1) and a novel candidate region at 4q31 by genome-wide scan in Chinese Hans.J Invest Dermatol. 2002; 119: 1361-1366Crossref PubMed Scopus (98) Google Scholar. It is possible that including the results from the Chinese Hans study (2002) in this meta-analysis may cause problems due to genetic heterogeneity between populations. But the top three bins were the same even when the data were re-analyzed without the Zhang et al., 2002Zhang X.J. He P.P. Wang Z.X. et al.Evidence for a major psoriasis susceptibility locus at 6p21 (PSORS1) and a novel candidate region at 4q31 by genome-wide scan in Chinese Hans.J Invest Dermatol. 2002; 119: 1361-1366Crossref PubMed Scopus (98) Google Scholar study. The region reported by Zhang et al., 2002Zhang X.J. He P.P. Wang Z.X. et al.Evidence for a major psoriasis susceptibility locus at 6p21 (PSORS1) and a novel candidate region at 4q31 by genome-wide scan in Chinese Hans.J Invest Dermatol. 2002; 119: 1361-1366Crossref PubMed Scopus (98) Google Scholar (chromosome 4q28–q31) had a nominal p-value of 1.69×10−3 even without the inclusion of their results, which, although not significant after a Bonferroni correction, suggests strong evidence for association between this region and psoriasis susceptibility in the Caucasian as well as the Chinese Hans population. Although 19 loci on 15 chromosomes have been published thus far as candidate regions, our meta-analysis only provided significant evidence for two chromosomal regions. The third-ranking bin on chromosome 6 (position 66–99 cM) is adjacent to the top-ranking bin and corresponds to the centromeric region of chromosome 6 covering 6p12 to 6q15. The evidence for this region indicates either the existence of a second susceptibility locus within this region as suggested by Capon et al., 2003Capon F. Toal I.K. Evans J.C. et al.Haplotype analysis of distantly related populations implicates corneodesmosin in psoriasis susceptibility.J Med Genet. 2003; 40: 447-452Crossref PubMed Scopus (39) Google Scholar or that the effect of PSORS1 can be detected in the adjacent bin. In Table III, we have listed the bins for the three most significant regions and have given for each of the studies the name of the most significant marker (if available), its position, and its p-value.Table IIISignificant psoriasis susceptibility regions as revealed by our meta-analysis with the position, name (if known), and p-value of the most significant marker found within that bin in each studyTrembath et al., 1997Trembath R.C. Clough R.L. Rosbotham J.L. et al.Identification of a major susceptibility locus on chromosome 6p and evidence for further disease loci revealed by a two stage genome-wide search in psoriasis.Hum Mol Genet. 1997; 6: 813-820Crossref PubMed Scopus (460) Google ScholarNair et al., 1997Nair R.P. Henseler T. Jenisch S. et al.Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan.Hum Mol Genet. 1997; 6: 1349-1356Crossref PubMed Scopus (373) Google ScholarSamuelsson et al., 1999Samuelsson L. Enlund F. Torinsson A. et al.A genome-wide search for genes predisposing to familial psoriasis by using a stratification approach.Hum Genet. 1999; 105: 523-529Crossref PubMed Scopus (105) Google ScholarLee et al., 2000Lee Y.-A. Ruschendorf F. Windemuth C. et al.Genome wide scan in German families reveals evidence for a novel psoriasis-susceptibility locus on chromosome 19p13.Am J Hum Genet. 2000; 67: 1020-1024Abstract Full Text Full Text PDF PubMed Scopus (129) Google ScholarVeal et al., 2001Veal C.D. Clough R.L. Barber R.C. et al.Identification of a novel psoriasis susceptibility locus at 1p and evidence of epistasis between PSORS1 and candidate loci.J Med Genet. 2001; 38: 7-13Crossref PubMed Scopus (124) Google ScholarZhang et al., 2002Zhang X.J. He P.P. Wang Z.X. et al.Evidence for a major psoriasis susceptibility locus at 6p21 (PSORS1) and a novel candidate region at 4q31 by genome-wide scan in Chinese Hans.J Invest Dermatol. 2002; 119: 1361-1366Crossref PubMed Scopus (98) Google ScholarChromosome 4 bin 132–165 cM157.9 cM (D4S413)153.6 cM (D4S1548)145 cM160.9 cM (D4S393)143.1 cM (D4S1565)159.1 cM (D4S2997)p=0.029p=0.0297p=0.077p=0.0787p=0.07p=0.0066Chromosome 6 bin 33–66 cM44.9 cM (D6S273)49.8 cM (D6S291)49 cM (D6S1019)34.3 cM (D6S422)44.9 cM (D6S273)48.3 cM (D6S1645)p=0.00071p=0.0217p=0.019p=0.0265p=0.00012p=0.00046Chromosome 6 bin 66–99 cM90 cM (D6S286)66.4 cM (D6S282)77 cM88.6 cM (D6S286)74.1 cM (D6S272)90 cM (D6S460)p=0.084p=0.1496p=0.032p=0.2182p=0.0000002p=0.0056The position in cM for each marker is the distance from the top of the chromosome linkage group (Dib et al., 1996Dib C. Faure S. Fizames C. et al.A comprehensive genetic map of the human genome based on 5,264 microsatellites.Nature. 1996; 380: 152-154Crossref PubMed Scopus (2725) Google Scholar; Broman et al., 1998Broman K.W. Murray J.C. Sheffield V.C. White R.L. Webber J.L. Comprehensive human genetic maps: Individual and sex-specific variation in recombination.Am J Hum Genet. 1998; 63: 861-869Abstract Full Text Full Text PDF PubMed Scopus (919) Google Scholar. Open table in a new tab The position in cM for each marker is the distance from the top of the chromosome linkage group (Dib et al., 1996Dib C. Faure S. Fizames C. et al.A comprehensive genetic map of the human genome based on 5,264 microsatellites.Nature. 1996; 380: 152-154Crossref PubMed Scopus (2725) Google Scholar; Broman et al., 1998Broman K.W. Murray J.C. Sheffield V.C. White R.L. Webber J.L. Comprehensive human genetic maps: Individual and sex-specific variation in recombination.Am J Hum Genet. 1998; 63: 861-869Abstract Full Text Full Text PDF PubMed Scopus (919) Google Scholar. Those loci that have been identified as potentially involved in psoriasis susceptibility in only one or two studies but are not picked up in our meta-analysis may be false positives, be peculiar to the population used or other studies may just lack the power to detect them. A large collaborative study was recently carried out by The International Psoriasis Genetics Consortium, 2003The International Psoriasis Genetics Consortium The international psoriasis genetics study: Assessing linkage to 14 candidate susceptibility loci in a cohort of 942 affected sib pairs.Am J Hum Genet. 2003; 73: 430-437Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, which used a very large sample size to overcome the problem of low power. This study provided unequivocal evidence for the major role of a gene or genes within the MHC but demonstrated no compelling support for non-MHC loci. It is also of note that the 19p13 locus was identified in two of the studies (Lee et al., 2000Lee Y.-A. Ruschendorf F. Windemuth C. et al.Genome wide scan in German families reveals evidence for a novel psoriasis-susceptibility locus on chromosome 19p13.Am J Hum Genet. 2000; 67: 1020-1024Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar; Veal et al., 2001Veal C.D. Clough R.L. Barber R.C. et al.Identification of a novel psoriasis susceptibility locus at 1p and evidence of epistasis between PSORS1 and candidate loci.J Med Genet. 2001; 38: 7-13Crossref PubMed Scopus (124) Google Scholar) and was recently further corroborated by an association scan involving 210 trios with early-onset psoriasis from Northern Germany (Hensen et al., 2003Hensen P. Windemuth C. Huffmeier U. et al.Association scan of the novel psoriasis susceptibility region on chromosome 19: Evidence for both susceptible and protective loci.Exp Dermatol. 2003; 12: 490-496Crossref PubMed Scopus (25) Google Scholar). It is therefore probable that the PSORS6 locus represents a founder mutation in Anglo-Saxons/North-Germans that occurred after the migration out of Africa. Another possible reason for the lack of replication of some results could be the large effect of the PSORS1 locus masking the other loci involved in psoriasis. Because of this potentially strong effect, we would suggest that future studies condition on the effect of the PSORS1 locus when conducting analysis. This could be done by stratifying samples into those segregating for the known disease locus (6p21) and those that do not. It is also possible to conduct a conditional analysis using methods such as those developed by Dudbridge, 2002Dudbridge F. Methods and software for association tests of uncertain haplotypes in case-parent trios.Am J Hum Genet. 2002; 71: A2338Google Scholar,Dudbridge, 2003Dudbridge F. Pedigree disequilibrium tests for multilocus haplotypes.Genet Epidemiol. 2003; 25: 115-121Crossref PubMed Scopus (1048) Google Scholar, and Cordell et al., 1995Cordell H.J. Todd J.A. Bennett S.T. Kawaguchi Y. Farrall M. Two-locus maximum LOD score analysis of a multifactorial trait: Joint consideration of IDDM2 and IDDM4 with IDDM1 in type 1 diabetes.Am J Hum Genet. 1995; 57: 920-934PubMed Google Scholar,Cordell et al., 2000Cordell H.J. Wedig G.C. Jacobs K.B. Elston R.C. Multilocus linkage tests based on affected relative pairs.Am J Hum Genet. 2000; 66: 1273-1286Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar. Using this type of method could lead to an even greater understanding of the genetic etiology of psoriasis. In conclusion, our meta-analysis of six published psoriasis genome-wide scans has provided further support for the susceptibility locus on chromosome 6p21, and suggests that the susceptibility locus on chromosome 4q31 (Zhang et al., 2002Zhang X.J. He P.P. Wang Z.X. et al.Evidence for a major psoriasis susceptibility locus at 6p21 (PSORS1) and a novel candidate region at 4q31 by genome-wide scan in Chinese Hans.J Invest Dermatol. 2002; 119: 1361-1366Crossref PubMed Scopus (98) Google Scholar) is important in the Caucasian as well as the Chinese Hans population. A meta-analysis using the GSMA method (Wise et al., 1999Wise L.H. Lanchbury J.S. Lewis C.M. Meta-analysis of genome searches.Ann Hum Genet. 1999; 63: 263-272Crossref PubMed Google Scholar) was conducted with the aim of identifying loci showing significant evidence of affecting psoriasis susceptibility across several studies. We were able to obtain the full results from five of the studies (Nair et al., 1997Nair R.P. Henseler T. Jenisch S. et al.Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan.Hum Mol Genet. 1997; 6: 1349-1356Crossref PubMed Scopus (373) Google Scholar; Trembath et al., 1997Trembath R.C. Clough R.L. Rosbotham J.L. et al.Identification of a major susceptibility locus on chromosome 6p and evidence for further disease loci revealed by a two stage genome-wide search in psoriasis.Hum Mol Genet. 1997; 6: 813-820Crossref PubMed Scopus (460) Google Scholar; Samuelsson et al., 1999Samuelsson L. Enlund F. Torinsson A. et al.A genome-wide search for genes predisposing to familial psoriasis by using a stratification approach.Hum Genet. 1999; 105: 523-529Crossref PubMed Scopus (105) Google Scholar; Lee et al., 2000Lee Y.-A. Ruschendorf F. Windemuth C. et al.Genome wide scan in German families reveals evidence for a novel psoriasis-susceptibility locus on chromosome 19p13.Am J Hum Genet. 2000; 67: 1020-1024Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar; Veal et al., 2001Veal C.D. Clough R.L. Barber R.C. et al.Identification of a novel psoriasis susceptibility locus at 1p and evidence of epistasis between PSORS1 and candidate loci.J Med Genet. 2001; 38: 7-13Crossref PubMed Scopus (124) Google Scholar). Unfortunately, data were not available from either the Capon et al., 1999Capon F. Novelli G. Semprini S. et al.Searching for psoriasis susceptibility genes in Italy: Genome scan and evidence for a new locus on chromosome 1.J Invest Dermatol. 1999; 112: 32-35Crossref PubMed Scopus (167) Google Scholar study or the Zhang et al., 2002Zhang X.J. He P.P. Wang Z.X. et al.Evidence for a major psoriasis susceptibility locus at 6p21 (PSORS1) and a novel candidate region at 4q31 by genome-wide scan in Chinese Hans.J Invest Dermatol. 2002; 119: 1361-1366Crossref PubMed Scopus (98) Google Scholar study. The Capon et al., 1999Capon F. Novelli G. Semprini S. et al.Searching for psoriasis susceptibility genes in Italy: Genome scan and evidence for a new locus on chromosome 1.J Invest Dermatol. 1999; 112: 32-35Crossref PubMed Scopus (167) Google Scholar study published the results for only four markers on chromosome 1q21, so this study could not be included in our analysis. But the Zhang et al., 2002Zhang X.J. He P.P. Wang Z.X. et al.Evidence for a major psoriasis susceptibility locus at 6p21 (PSORS1) and a novel candidate region at 4q31 by genome-wide scan in Chinese Hans.J Invest Dermatol. 2002; 119: 1361-1366Crossref PubMed Scopus (98) Google Scholar study could be included in our analysis as we were able to assign ranks to the eight most significant bins reported in the paper, with the remaining bins being assigned equal rank as described in Wise et al., 1999Wise L.H. Lanchbury J.S. Lewis C.M. Meta-analysis of genome searches.Ann Hum Genet. 1999; 63: 263-272Crossref PubMed Google Scholar. The genome-wide studies conducted by Tomfohrde et al., 1994Tomfohrde J. Silverman A. Barnes R. et al.Gene for familial psoriasis susceptibility mapped to the distal end of human chromosome 17q.Science. 1994; 264: 1141-1145Crossref PubMed Scopus (380) Google Scholar, and Asumalahti et al., 2003Asumalahti K. Latitinen T. Lahermo P. et al.Psoriasis susceptibility locus on 18p revealed by genome scan in Finnish families not associated with PSORS1.J Invest Dermatol. 2003; 121: 735-740Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar were not included in our analysis. These studies involved only a small number of families (8, 1, and 9, respectively), and we felt that the problems involved in accounting for differences in sample size between studies outweighed the information to be gained from them. Furthermore,Asumalahti et al., 2003Asumalahti K. Latitinen T. Lahermo P. et al.Psoriasis susceptibility locus on 18p revealed by genome scan in Finnish families not associated with PSORS1.J Invest Dermatol. 2003; 121: 735-740Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar selected only PSORS1-negative families for their genome-wide scan, which would have biased the meta-analysis. The studies used in our meta-analysis differed in some aspects of design such as the number of families within each study, the number of markers, and the disease criteria used. Five of the six studies used in our meta-analysis are of a similar ethnic background (Caucasian), whereas Zhang et al., 2002Zhang X.J. He P.P. Wang Z.X. et al.Evidence for a major psoriasis susceptibility locus at 6p21 (PSORS1) and a novel candidate region at 4q31 by genome-wide scan in Chinese Hans.J Invest Dermatol. 2002; 119: 1361-1366Crossref PubMed Scopus (98) Google Scholar used the Chinese Hans population in their study. The main characteristics of the six studies are summarized in Table IV.Table IVSummary of the studies used in the meta-analysisTrembath et al., 1997Trembath R.C. Clough R.L. Rosbotham J.L. et al.Identification of a major susceptibility locus on chromosome 6p and evidence for further disease loci revealed by a two stage genome-wide search in psoriasis.Hum Mol Genet. 1997; 6: 813-820Crossref PubMed Scopus (460) Google ScholarNair et al., 1997Nair R.P. Henseler T. Jenisch S. et al.Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan.Hum Mol Genet. 1997; 6: 1349-1356Crossref PubMed Scopus (373) Google ScholarSamuelsson et al., 1999Samuelsson L. Enlund F. Torinsson A. et al.A genome-wide search for genes predisposing to familial psoriasis by using a stratification approach.Hum Genet. 1999; 105: 523-529Crossref PubMed Scopus (105) Google ScholarLee et al., 2000Lee Y.-A. Ruschendorf F. Windemuth C. et al.Genome wide scan in German families reveals evidence for a novel psoriasis-susceptibility locus on chromosome 19p13.Am J Hum Genet. 2000; 67: 1020-1024Abstract Full Text Full Text PDF PubMed Scopus (129) Google ScholarVeal et al., 2001Veal C.D. Clough R.L. Barber R.C. et al.Identification of a novel psoriasis susceptibility locus at 1p and evidence of epistasis between PSORS1 and candidate loci.J Med Genet. 2001; 38: 7-13Crossref PubMed Scopus (124) Google ScholarZhang et al., 2002Zhang X.J. He P.P. Wang Z.X. et al.Evidence for a major psoriasis susceptibility locus at 6p21 (PSORS1) and a novel candidate region at 4q31 by genome-wide scan in Chinese Hans.J Invest Dermatol. 2002; 119: 1361-1366Crossref PubMed Scopus (98) Google ScholarPopulationEuropeanAmerican and GermanSwedishGermanBritishChinese HansNumber of families41 multiplex families (66ASP), 262 individuals115 families (182ASP), 726 individuals86 families (134ASP), 366 individuals32 extended families, 367 individuals158 nuclear families (284ASP), 767 individuals61 multiplex families, 189 affected individualsNumber of markers260287390370271304Disease subtypes included in study94% chronic plaque, 3% guttate, 3% palmoplantar92% type 1 psoriasis (AAO <40)71% psoriasis vulgaris, 29% psoriasis arthritisNo psoriasis pustulosa familiesNo comment made100% psoriasis vulgarisASP, Affected sub pair; AAO, Age at onset Open table in a new tab ASP, Affected sub pair; AAO, Age at onset The GSMA method (Wise et al., 1999Wise L.H. Lanchbury J.S. Lewis C.M. Meta-analysis of genome searches.Ann Hum Genet. 1999; 63: 263-272Crossref PubMed Google Scholar) uses a non-parametric ranking method to identify genetic regions with consistently increased sharing statistics. The genome is divided into distinct regions (bins) and the evidence for linkage within each bin is evaluated across the studies. We initially applied the GSMA method to the six psoriasis genome-wide studies (Nair et al., 1997Nair R.P. Henseler T. Jenisch S. et al.Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan.Hum Mol Genet. 1997; 6: 1349-1356Crossref PubMed Scopus (373) Google Scholar; Trembath et al., 1997Trembath R.C. Clough R.L. Rosbotham J.L. et al.Identification of a major susceptibility locus on chromosome 6p and evidence for further disease loci revealed by a two stage genome-wide search in psoriasis.Hum Mol Genet. 1997; 6: 813-820Crossref PubMed Scopus (460) Google Scholar; Samuelsson et al., 1999Samuelsson L. Enlund F. Torinsson A. et al.A genome-wide search for genes predisposing to familial psoriasis by using a stratification approach.Hum Genet. 1999; 105: 523-529Crossref PubMed Scopus (105) Google Scholar; Lee et al., 2000Lee Y.-A. Ruschendorf F. Windemuth C. et al.Genome wide scan in German families reveals evidence for a novel psoriasis-susceptibility locus on chromosome 19p13.Am J Hum Genet. 2000; 67: 1020-1024Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar; Veal et al., 2001Veal C.D. Clough R.L. Barber R.C. et al.Identification of a novel psoriasis susceptibility locus at 1p and evidence of epistasis between PSORS1 and candidate loci.J Med Genet. 2001; 38: 7-13Crossref PubMed Scopus (124) Google Scholar; Zhang et al., 2002Zhang X.J. He P.P. Wang Z.X. et al.Evidence for a major psoriasis susceptibility locus at 6p21 (PSORS1) and a novel candidate region at 4q31 by genome-wide scan in Chinese Hans.J Invest Dermatol. 2002; 119: 1361-1366Crossref PubMed Scopus (98) Google Scholar), with the assumption that the results from each genome search contributed equally to the meta-analysis. The genome was divided into 110 bins of approximately equal size in each of the six studies. A bin width of 33 cM was decided upon because this was the smallest genetic interval that gave at least one marker in each bin in every study. In case there was genetic heterogeneity between the Caucasian and Chinese Hans populations, we repeated the meta-analysis using the results from the five Caucasian studies (Nair et al., 1997Nair R.P. Henseler T. Jenisch S. et al.Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan.Hum Mol Genet. 1997; 6: 1349-1356Crossref PubMed Scopus (373) Google Scholar; Trembath et al., 1997Trembath R.C. Clough R.L. Rosbotham J.L. et al.Identification of a major susceptibility locus on chromosome 6p and evidence for further disease loci revealed by a two stage genome-wide search in psoriasis.Hum Mol Genet. 1997; 6: 813-820Crossref PubMed Scopus (460) Google Scholar; Samuelsson et al., 1999Samuelsson L. Enlund F. Torinsson A. et al.A genome-wide search for genes predisposing to familial psoriasis by using a stratification approach.Hum Genet. 1999; 105: 523-529Crossref PubMed Scopus (105) Google Scholar; Lee et al., 2000Lee Y.-A. Ruschendorf F. Windemuth C. et al.Genome wide scan in German families reveals evidence for a novel psoriasis-susceptibility locus on chromosome 19p13.Am J Hum Genet. 2000; 67: 1020-1024Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar; Veal et al., 2001Veal C.D. Clough R.L. Barber R.C. et al.Identification of a novel psoriasis susceptibility locus at 1p and evidence of epistasis between PSORS1 and candidate loci.J Med Genet. 2001; 38: 7-13Crossref PubMed Scopus (124) Google Scholar). In addition to excluding the Chinese Hans study, we tested the robustness of our results by excluding one Caucasian population study at a time and repeating the meta-analysis. Financial support for this work was provided by a University of Sheffield Studentship (for GSS). We thank all the groups involved in this study for generously providing the results of the individual psoriasis genome-wide studies.

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