Title: The International Psoriasis Genetics Study: Assessing Linkage to 14 Candidate Susceptibility Loci in a Cohort of 942 Affected Sib Pairs
Abstract: In an effort to confirm previously reported linkages to psoriasis, we analyzed 942 affected sibling pairs (ASPs) from 710 pedigrees for 53 polymorphic microsatellites spanning 14 psoriasis candidate regions at an intermarker spacing of ∼5 cM. Maximum LOD score (MLS) analysis of ASPs yielded allele sharing of 60% for markers within the major histocompatibility complex (MHC) (P=2×10−14), which yielded a gene-specific λs of 1.6. Across the remainder of the genome, the strongest evidence of allele sharing was obtained on chromosomes 16q (D16S3032; MLS=1.3; P=.007) and 10q22–q23 (D10S2327; MLS=1.1; P=.012). None of the remaining loci exceeded MLS=0.9, the value expected to occur by chance once in this study. In agreement with previous studies, strong linkage disequilibrium was also observed between psoriasis and the MHC (pedigree disequilibrium test P=3.9×10−8 for D6S1014). Two psoriasis-associated MHC haplotypes were identified with the haplotype-based transmission/disequilibrium test. Analysis of only those families carrying either of these haplotypes significantly increased the chromosome 16q LOD score from 1.3 to 2.4 (P=.045). These results underscore the importance of the MHC in psoriasis and provide a rationale for more-detailed examination of candidate regions on chromosomes 16q and 10q. In an effort to confirm previously reported linkages to psoriasis, we analyzed 942 affected sibling pairs (ASPs) from 710 pedigrees for 53 polymorphic microsatellites spanning 14 psoriasis candidate regions at an intermarker spacing of ∼5 cM. Maximum LOD score (MLS) analysis of ASPs yielded allele sharing of 60% for markers within the major histocompatibility complex (MHC) (P=2×10−14), which yielded a gene-specific λs of 1.6. Across the remainder of the genome, the strongest evidence of allele sharing was obtained on chromosomes 16q (D16S3032; MLS=1.3; P=.007) and 10q22–q23 (D10S2327; MLS=1.1; P=.012). None of the remaining loci exceeded MLS=0.9, the value expected to occur by chance once in this study. In agreement with previous studies, strong linkage disequilibrium was also observed between psoriasis and the MHC (pedigree disequilibrium test P=3.9×10−8 for D6S1014). Two psoriasis-associated MHC haplotypes were identified with the haplotype-based transmission/disequilibrium test. Analysis of only those families carrying either of these haplotypes significantly increased the chromosome 16q LOD score from 1.3 to 2.4 (P=.045). These results underscore the importance of the MHC in psoriasis and provide a rationale for more-detailed examination of candidate regions on chromosomes 16q and 10q. Psoriasis (MIM 177900) is an inflammatory, hyperproliferative disorder of the skin, the pathogenesis of which remains poorly understood (Barker Barker, 1998Barker JN Pathogenesis of psoriasis.J Dermatol. 1998; 25: 778-781Crossref PubMed Scopus (16) Google Scholar; Elder Elder, 1998Elder JT Psoriasis.in: Jameson JL Principles of molecular medicine. Humana, Totowa, NJ1998: 793-800Crossref Google Scholar). Psoriasis is common, affecting >2% of adults in most populations, yet current therapeutic strategies remain suboptimal (Camp Camp, 1998Camp RDR Psoriasis.in: Champion RH Burton JL Burns DA Breathnach SM Textbook of dermatology. Vol 2. Blackwell, London1998: 1589-1650Google Scholar). Susceptibility to the development of psoriasis has a significant genetic component, with the λs, a measure of the risk ratio of disease in siblings of affected subjects, reported to be in the range 4–6 (Bhalerao and Bowcock Bhalerao and Bowcock, 1998Bhalerao J Bowcock AM The genetics of psoriasis: a complex disorder of the skin and immune system.Hum Mol Genet. 1998; 7: 1537-1545Crossref PubMed Scopus (230) Google Scholar; Elder et al. Elder et al., 2001Elder JT Nair RP Henseler T Jenisch S Stuart P Chia N Christophers E Voorhees JJ The genetics of psoriasis 2001: the odyssey continues.Arch Dermatol. 2001; 137: 1447-1454Crossref PubMed Google Scholar). Psoriasis appears to be a disorder of complex etiology that requires the interaction of unknown environmental triggers and genetic susceptibility (Elder et al. Elder et al., 2001Elder JT Nair RP Henseler T Jenisch S Stuart P Chia N Christophers E Voorhees JJ The genetics of psoriasis 2001: the odyssey continues.Arch Dermatol. 2001; 137: 1447-1454Crossref PubMed Google Scholar; Capon et al. 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 (135) Google Scholar). Resolution of the molecular genetic contributions to the pathogenesis of psoriasis will provide a logical framework against which future advances in treatment and/or prevention are likely to evolve. In recent years, a number of genomewide linkage scans have been performed, by use of family material ascertained from dispersed geographical locations. In no fewer than five studies, significant evidence of linkage has been reported for PSORS1 (psoriasis susceptibility 1) a region located on the short arm of chromosome 6 and specifically within the major histocompatibility complex (MHC) (Nair et al. Nair et al., 1997Nair RP Henseler T Jenisch S Stuart P Bichakjian CK Lenk W Westphal E Guo SW Christophers E Voorhees JJ Elder JT 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 (357) Google Scholar; Trembath et al. Trembath et al., 1997Trembath RC Clough RL Rosbotham JL Jones AB Camp RD Frodsham A Browne J Barber R Terwilliger J Lathrop GM Barker JN 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 (440) Google Scholar; Samuelsson et al. Samuelsson et al., 1999Samuelsson L Enlund F Torinsson A Yhr M Inerot A Enerback C Wahlstrom J Swanbeck G Martinsson T 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. Lee et al., 2000Lee Y-A Rüschendorf F Windemuth C Schmitt-Egenolf M Stadelmann A Nürnberg G Ständer M Wienker TF Reis A Traupe H Genomewide 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 (128) Google Scholar; Veal et al. Veal et al., 2001Veal CD Clough RL Barber RC Mason S Tillman D Ferry B Jones AB Ameen M Balendran N Powis SH Burden AD Barker JN Trembath RC 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 (122) Google Scholar; Zhang et al. Zhang et al., 2002Zhang XJ He PP Wang ZX Zhang J Li YB Wang HY Wei SC Chen SY Xu SJ Jin L Yang S Huang W 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 (95) Google Scholar). Further linkage disequilibrium–mapping studies, including the use of non-MHC gene polymorphic markers, when taken together, localize PSORS1 to a genomic segment ∼150 kb in length. This region includes the class 1 MHC gene HLA-C and the gene that encodes corneodesmosin, a component of the keratinocyte desmosome (Balendran et al. Balendran et al., 1999Balendran N Clough RL Arguello JR Barber R Veal C Jones AB Rosbotham JL Little AM Madrigal A Barker JN Powis SH Trembath RC Characterization of the major susceptibility region for psoriasis at chromosome 6p21.3.J Invest Dermatol. 1999; 113: 322-328Crossref PubMed Scopus (96) Google Scholar; Oka et al. Oka et al., 1999Oka A Tamiya G Tomizawa M Ota M Katsuyama Y Makino S Shiina T Yoshitome M Iizuka M Sasao Y Iwashita K Kawakubo Y Sugai J Ozawa A Ohkido M Kimura M Bahram S Inoko H Association analysis using refined microsatellite markers localizes a susceptibility locus for psoriasis vulgaris within a 111 kb segment telomeric to the HLA-C gene.Hum Mol Genet. 1999; 8: 2165-2170Crossref PubMed Scopus (149) Google Scholar; Nair et al. Nair et al., 2000Nair RP Stuart P Henseler T Jenisch S Chia NVC Westphal E Schork NJ Kim J Lim HW Christophers E Voorhees JJ Elder JT Localization of psoriasis-susceptibility locus PSORS1 to a 60-kb interval telomeric to HLA-C.Am J Hum Genet. 2000; 66: 1833-1844Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar). Intensive genetic studies to identify risk haplotypes from this region are now under way (Nair et al. Nair et al., 2000Nair RP Stuart P Henseler T Jenisch S Chia NVC Westphal E Schork NJ Kim J Lim HW Christophers E Voorhees JJ Elder JT Localization of psoriasis-susceptibility locus PSORS1 to a 60-kb interval telomeric to HLA-C.Am J Hum Genet. 2000; 66: 1833-1844Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar; Veal et al. Veal et al., 2002Veal CD Capon F Allen MH Heath EK Evans JC Jones A Patel S Burden D Tillman D Barker JNWN Trembath RC Family-based analysis using a dense single-nucleotide polymorphism–based map defines genetic variation at PSORS1, the major psoriasis-susceptibility locus.Am J Hum Genet. 2002; 71: 554-564Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar). However, initial assessment of allele sharing between affected sibling pairs suggests that the PSORS1 locus may account for no more than 50% of the sibling relative risk (Trembath et al. Trembath et al., 1997Trembath RC Clough RL Rosbotham JL Jones AB Camp RD Frodsham A Browne J Barber R Terwilliger J Lathrop GM Barker JN 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 (440) Google Scholar), which supports the view that, in addition to potential environmental triggers for disease onset, susceptibility is dependent on the role of other genetic loci. To date, at least seven regions outside of the MHC (PSORS2–8) have been proposed to harbor psoriasis susceptibility loci, on the basis of genomewide linkage scans (Tomfohrde et al. Tomfohrde et al., 1994Tomfohrde J Silverman A Barnes R Fernandez-Vina MA Young M Lory D Morris L Wuepper KD Stastny P Menter A Bowcock AM Gene for familial psoriasis susceptibility mapped to the distal end of human chromosome 17q.Science. 1994; 264: 1141-1145Crossref PubMed Scopus (363) Google Scholar; Matthews et al. Matthews et al., 1996Matthews D Fry L Powles A Weber J McCarthy M Fisher E Davies K Williamson R Evidence that a locus for familial psoriasis maps to chromosome 4q.Nat Genet. 1996; 14: 231-233Crossref PubMed Scopus (183) Google Scholar; Nair et al. Nair et al., 1997Nair RP Henseler T Jenisch S Stuart P Bichakjian CK Lenk W Westphal E Guo SW Christophers E Voorhees JJ Elder JT 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 (357) Google Scholar; Capon et al. Capon et al., 1999Capon F Novelli G Semprini S Clementi M Nudo M Vultaggio P Mazzanti C Gobello T Botta A Fabrizi G Dallapiccola B 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 (162) Google Scholar; Samuelsson et al. Samuelsson et al., 1999Samuelsson L Enlund F Torinsson A Yhr M Inerot A Enerback C Wahlstrom J Swanbeck G Martinsson T 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. Lee et al., 2000Lee Y-A Rüschendorf F Windemuth C Schmitt-Egenolf M Stadelmann A Nürnberg G Ständer M Wienker TF Reis A Traupe H Genomewide 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 (128) Google Scholar; Veal et al. Veal et al., 2001Veal CD Clough RL Barber RC Mason S Tillman D Ferry B Jones AB Ameen M Balendran N Powis SH Burden AD Barker JN Trembath RC 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 (122) Google Scholar). Support for a putative susceptibility locus is greatly enhanced by replication (at a statistically significant level) in independent data sets. Indeed, this process is perceived as a critical strategy to aid distinction from false-positive linkages, in the data sets generated by marker-dense genomewide analyses (Lander and Kruglyak Lander and Kruglyak, 1995Lander E Kruglyak L Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results.Nat Genet. 1995; 11: 241-247Crossref PubMed Scopus (4378) Google Scholar). An alternative strategy is to analyze very large samples (Risch Risch, 2000Risch NJ Searching for genetic determinants in the new millennium.Nature. 2000; 405: 847-856Crossref PubMed Scopus (1531) Google Scholar). This strategy is aimed at overcoming the low power inherent in diseases characterized by low-penetrance, high-prevalence susceptibility loci. All such studies require careful attention to population selection so as to minimize the effects of ethnic and clinical heterogeneity. To better understand the genetics of psoriasis, we have established a consortium of investigators to investigate 14 previously reported potential psoriasis-susceptibility loci in a cohort of 710 families with psoriasis. Although the subjects have been ascertained across broad geographical regions, the vast majority of patients and relatives are of European descent. Subjects.—The International Psoriasis Genetics Consortium patient cohort consists of independently ascertained pedigrees, providing a total of 942 affected sib pairs (ASPs). Details are presented in table 1 and table 2. All families were recruited by experienced consortium members (based in Dallas/St. Louis; Ann Arbor/Kiel, Germany; and London/Leicester/Glasgow), by use of criteria as described in detail elsewhere (Tomfohrde et al. Tomfohrde et al., 1994Tomfohrde J Silverman A Barnes R Fernandez-Vina MA Young M Lory D Morris L Wuepper KD Stastny P Menter A Bowcock AM Gene for familial psoriasis susceptibility mapped to the distal end of human chromosome 17q.Science. 1994; 264: 1141-1145Crossref PubMed Scopus (363) Google Scholar; Nair et al. Nair et al., 1997Nair RP Henseler T Jenisch S Stuart P Bichakjian CK Lenk W Westphal E Guo SW Christophers E Voorhees JJ Elder JT 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 (357) Google Scholar; Trembath et al. Trembath et al., 1997Trembath RC Clough RL Rosbotham JL Jones AB Camp RD Frodsham A Browne J Barber R Terwilliger J Lathrop GM Barker JN 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 (440) Google Scholar). The Ann Arbor/Kiel data set included 221 ASPs typed in a genome scan performed by Nair and colleagues (Nair et al., 1997Nair RP Henseler T Jenisch S Stuart P Bichakjian CK Lenk W Westphal E Guo SW Christophers E Voorhees JJ Elder JT 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 (357) Google Scholar), together with a further 140 ASPs recruited for this study. The London/Leicester cohort included family material described by Veal and colleagues (Veal et al., 2001Veal CD Clough RL Barber RC Mason S Tillman D Ferry B Jones AB Ameen M Balendran N Powis SH Burden AD Barker JN Trembath RC 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 (122) Google Scholar), with no duplication of the data set used by the same group in an initial genome scan (Trembath et al. Trembath et al., 1997Trembath RC Clough RL Rosbotham JL Jones AB Camp RD Frodsham A Browne J Barber R Terwilliger J Lathrop GM Barker JN 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 (440) Google Scholar). The Dallas/St. Louis sample comprised 238 pedigrees and specifically did not include the multiply affected families used in the scan that localized PSORS2 on 17q (Tomfohrde et al. Tomfohrde et al., 1994Tomfohrde J Silverman A Barnes R Fernandez-Vina MA Young M Lory D Morris L Wuepper KD Stastny P Menter A Bowcock AM Gene for familial psoriasis susceptibility mapped to the distal end of human chromosome 17q.Science. 1994; 264: 1141-1145Crossref PubMed Scopus (363) Google Scholar). The three groups used comparable diagnostic criteria and excluded case subjects where palmo-plantar pustulosis or seborrheic dermatitis occurred in the absence of other clinical signs of psoriasis (Camp Camp, 1998Camp RDR Psoriasis.in: Champion RH Burton JL Burns DA Breathnach SM Textbook of dermatology. Vol 2. Blackwell, London1998: 1589-1650Google Scholar).Table 1The Consortium Data Set: Sample CompositionCohortNo. of PedigreesNo. of ASPsOriginLondon/Leicester/Glasgow228349United KingdomAnn Arbor/Kiel244361United States, GermanyDallas/St. Louis238232United States Total710942 Open table in a new tab Table 2The Consortium Data Set: Pedigree StructuresNo. of Affected SubjectsFamily TypeNo. of Families123456⩾7Nuclear5663832017631210Extended144 0 14 4329261218 Total7103833421960281318 Open table in a new tab Each group obtained approval for these studies from its own institutional review board or ethics committee (U.K.). All subjects participating in this study provided informed consent. Genotyping.—The candidate regions were defined as (i) any locus identified by genome scans published at the outset of the study and (ii) loci that had displayed suggestive evidence of linkage in at least one genome scan, including unpublished surveys by Consortium members. All 14 regions that met these criteria are reported in table 3. A total of 53 polymorphic microsatellites spanning the candidate loci at an average of 5-cM intervals (table 3) were selected from the Marshfield (Broman et al. Broman et al., 1998Broman KW Murray JC Sheffield VC White RL Weber JL 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 (892) Google Scholar) and Généthon (Dib et al. Dib et al., 1996Dib C Faure S Fizames C Samson D Drouot N Vignal A Millasseau P Marc S Hazan J Seboun E Lathrop M Gyapay G Morissette J Weissenbach J A comprehensive genetic map of the human genome based on 5,264 microsatellites.Nature. 1996; 380: 152-154Crossref PubMed Scopus (2668) Google Scholar) marker sets. Genotyping was performed by the London/Leicester and Dallas/St. Louis groups by use of fluorescent dyes (Trembath et al. Trembath et al., 1997Trembath RC Clough RL Rosbotham JL Jones AB Camp RD Frodsham A Browne J Barber R Terwilliger J Lathrop GM Barker JN 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 (440) Google Scholar), with electrophoresis and signal recording performed on ABI 377 automated sequencers (Applied Biosystems). The Ann Arbor/Kiel group performed genotyping using 32P labeling of a single primer, as described elsewhere (Nair et al. Nair et al., 1997Nair RP Henseler T Jenisch S Stuart P Bichakjian CK Lenk W Westphal E Guo SW Christophers E Voorhees JJ Elder JT 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 (357) Google Scholar). CEPH individual 1347-02 was genotyped by all three groups as a standard for comparison. Completeness of genotyping varied from group to group and from marker to marker, with a range of 66%–95% in the pooled sample. Mendelian inconsistencies in pedigree data were identified and eliminated by the PedCheck software (O’Connell and Weeks O’Connell and Weeks, 1998O’Connell JR Weeks DE PedCheck: a program for identification of genotype incompatibilities in linkage analysis.Am J Hum Genet. 1998; 63: 259-266Abstract Full Text Full Text PDF PubMed Scopus (1806) Google Scholar).Table 3Psoriasis Susceptibility Regions Typed in Consortium Data SetRegion and MarkerDistance from pter (cM)MLSMASReferences1q21 (PSORS4):Bhalerao and Bowcock Bhalerao and Bowcock, 1998Bhalerao J Bowcock AM The genetics of psoriasis: a complex disorder of the skin and immune system.Hum Mol Genet. 1998; 7: 1537-1545Crossref PubMed Scopus (230) Google Scholar; Capon et al. Capon et al., 1999Capon F Novelli G Semprini S Clementi M Nudo M Vultaggio P Mazzanti C Gobello T Botta A Fabrizi G Dallapiccola B 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 (162) Google Scholar D1S1679235.8.6.52 APOA2243.865.3.51 D1S1677245.44.6.522p:Trembath et al. Trembath et al., 1997Trembath RC Clough RL Rosbotham JL Jones AB Camp RD Frodsham A Browne J Barber R Terwilliger J Lathrop GM Barker JN 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 (440) Google Scholar; Bhalerao and Bowcock Bhalerao and Bowcock, 1998Bhalerao J Bowcock AM The genetics of psoriasis: a complex disorder of the skin and immune system.Hum Mol Genet. 1998; 7: 1537-1545Crossref PubMed Scopus (230) Google Scholar D2S134289.3750.5 D2S13690.7350.5 D2S134aMarkers D2S134 and D17S688 were not typed for the Ann Arbor/Kiel group.105.870.5 D2S1772106.9650.54q13:Bhalerao and Bowcock Bhalerao and Bowcock, 1998Bhalerao J Bowcock AM The genetics of psoriasis: a complex disorder of the skin and immune system.Hum Mol Genet. 1998; 7: 1537-1545Crossref PubMed Scopus (230) Google Scholar D4S427178.775.3.52 D4S2394182.01.4.524q21:Samuelsson et al. Samuelsson et al., 1999Samuelsson L Enlund F Torinsson A Yhr M Inerot A Enerback C Wahlstrom J Swanbeck G Martinsson T 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 D4S1548214.455.4.52 D4S1629221.34.5.52 D4S1554262.02.2.514qter (PSORS3):Matthews et al. Matthews et al., 1996Matthews D Fry L Powles A Weber J McCarthy M Fisher E Davies K Williamson R Evidence that a locus for familial psoriasis maps to chromosome 4q.Nat Genet. 1996; 14: 231-233Crossref PubMed Scopus (183) Google Scholar D4S1535266.995.2.51 D4S171274.875.3.516p21 (PSORS1):Nair et al. Nair et al., 1997Nair RP Henseler T Jenisch S Stuart P Bichakjian CK Lenk W Westphal E Guo SW Christophers E Voorhees JJ Elder JT 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 (357) Google Scholar; Trembath et al. Trembath et al., 1997Trembath RC Clough RL Rosbotham JL Jones AB Camp RD Frodsham A Browne J Barber R Terwilliger J Lathrop GM Barker JN 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 (440) Google Scholar; Samuelsson et al. Samuelsson et al., 1999Samuelsson L Enlund F Torinsson A Yhr M Inerot A Enerback C Wahlstrom J Swanbeck G Martinsson T 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 TNFB83.5112.1.59 D6S27384.12512.6.59 D6S101484.63512.6.59 D6S29184.9311.1.596q:Nair et al. Nair et al., 1997Nair RP Henseler T Jenisch S Stuart P Bichakjian CK Lenk W Westphal E Guo SW Christophers E Voorhees JJ Elder JT 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 (357) Google Scholar D6S270184.57.7.53 GATA184A08198.07.4.528q24:Trembath et al. Trembath et al., 1997Trembath RC Clough RL Rosbotham JL Jones AB Camp RD Frodsham A Browne J Barber R Terwilliger J Lathrop GM Barker JN 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 (440) Google Scholar D8S1128191.0150.5 D8S1801195.1850.51 D8S284197.495.1.51 D8S558200.56.2.5110q22:Nair et al. Nair et al., 1997Nair RP Henseler T Jenisch S Stuart P Bichakjian CK Lenk W Westphal E Guo SW Christophers E Voorhees JJ Elder JT 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 (357) Google Scholar D10S1136126.955.9.53 D10S569133.3651.1.53 D10S2327137.3151.1.5311p13:Nair et al. Nair et al., 1997Nair RP Henseler T Jenisch S Stuart P Bichakjian CK Lenk W Westphal E Guo SW Christophers E Voorhees JJ Elder JT 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 (357) Google Scholar D11S93581.55.4.52 D11S133084.915.4.52 D11S136087.51.3.52 D11S90390.995.2.5114q31:Bhalerao and Bowcock Bhalerao and Bowcock, 1998Bhalerao J Bowcock AM The genetics of psoriasis: a complex disorder of the skin and immune system.Hum Mol Genet. 1998; 7: 1537-1545Crossref PubMed Scopus (230) Google Scholar D14S617123.680.5 D14S81128.225.3.51 D14S1142130.735.1.51 D14S1434134.460.516q:Nair et al. Nair et al., 1997Nair RP Henseler T Jenisch S Stuart P Bichakjian CK Lenk W Westphal E Guo SW Christophers E Voorhees JJ Elder JT 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 (357) Google Scholar D16S339691.84.6.52 D16S77092.3.6.52 D16S41596.635.6.52 D16S303499.625.6.52 D16S771100.38.5.52 D16S3032102.621.3.5317q25 (PSORS2):Tomfohrde et al. Tomfohrde et al., 1994Tomfohrde J Silverman A Barnes R Fernandez-Vina MA Young M Lory D Morris L Wuepper KD Stastny P Menter A Bowcock AM Gene for familial psoriasis susceptibility mapped to the distal end of human chromosome 17q.Science. 1994; 264: 1141-1145Crossref PubMed Scopus (363) Google Scholar; Nair et al. Nair et al., 1997Nair RP Henseler T Jenisch S Stuart P Bichakjian CK Lenk W Westphal E Guo SW Christophers E Voorhees JJ Elder JT 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 (357) Google Scholar; Enlund et al. Enlund et al., 1999Enlund F Samuelsson L Enerback C Inerot A Wahlstrom J Yhr M Torinsson A Riley J Swanbeck G Martinsson T Psoriasis susceptibility locus in chromosome region 3q21 identified in patients from southwest Sweden.Eur J Hum Genet. 1999; 7: 783-790Crossref PubMed Scopus (118) Google Scholar D17S2059112.475.2.52 D17S1301122.795.7.53 D17S674141.935.3.52 D17S784161.5350.5 D17S668aMarkers D2S134 and D17S688 were not typed for the Ann Arbor/Kiel group.179.8250.5 D17S928179.8250.520p:Nair et al. Nair et al., 1997Nair RP Henseler T Jenisch S Stuart P Bichakjian CK Lenk W Westphal E Guo SW Christophers E Voorhees JJ Elder JT 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 (357) Google Scholar; Trembath et al. Trembath et al., 1997Trembath RC Clough RL Rosbotham JL Jones AB Camp RD Frodsham A Browne J Barber R Terwilliger J Lathrop GM Barker JN 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 (440) Google Scholar D20S87949.915.1.51 D20S85152.12.1.51 D20S16053.9850.5 D20S89457.0150.51 D20S18657.8250.5 D20S60459.920.5a Markers D2S134 and D17S688 were not typed for the Ann Arbor/Kiel group. Open table in a new tab Statistical analyses.—Allele sharing in affected siblings was assessed by use of Risch’s maximum LOD score (MLS) method (Risch Risch, 1990Risch N Linkage strategies for genetically complex traits. I. Multilocus models.Am J Hum Genet. 1990; 46: 222-228PubMed Google Scholar), as implemented in a modification of GENEHUNTER 2.1 (Kruglyak et al. Kruglyak et al., 1996Kruglyak L Daly MJ Reeve-Daly MP Lander ES Parametric and nonparametric linkage analysis: a unified multipoint approach.