Psoriasis (OMIM#177900) is a chronic in ammatory

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1 ORIGINAL ARTICLE See related Editorial on page v Psoriasis Susceptibility Locus on 18p Revealed by Genome Scan in Finnish Families Not Associated with PSORS1 Kati Asumalahti, Tarja Laitinen, PÌivi Lahermo,w Sari Suomela,z Raija Itkonen-Vatjus,y Christer Jansen,yy Jaakko Karvonen,y Seija-Liisa Karvonen,y Timo Reunala,z Erna Snellman,# Tutta Uurasmaa,yy Ulpu Saarialho-Kere,z and Juha Kere, Department of Medical Genetics and wfinnish Genome Center, University of Helsinki, Helsinki, Finland; zdepartment of Dermatology, Helsinki University Central Hospital, Helsinki, Finland; ydepartment of Dermatology, Oulu University Central Hospital, Oulu, Finland; yydepartment of Dermatology, Turku University Central Hospital, Turku, Finland; zdepartment of Dermatology, Tampere University Hospital, Tampere, Finland; #Department of Dermatology, PÌijÌt-HÌme Central Hospital, Lahti, Finland; Department of Biosciences at Novum and Clinical Research Center, Karolinska Institute, Huddinge, Sweden The major susceptibility locus for psoriasis, PSORS1, resides on chromosome 6p and includes the candidate genes HLA-C, HCR, and CDSN. Based on a nationwide collection of psoriasis patients and genotyping for the PSORS1 susceptibility haplotype, we selected for a genome scan nine families who do not show association with PSORS1 to more easily detect minor loci for psoriasis susceptibility. In the genome scan, ve loci gave initial evidence of linkage and were studied with a denser marker map. After ne mapping, only one locus on 18p11.23 showed suggestive evidence of linkage (nonparametric multipoint linkage analysis score, 3.58; p ¼ ). The bootstrapping analysis showed that one large family contributed the majority of the linkage (p ¼ ), but was supported by other families. Haplotype sharing between the linked families and haplotype association analysis gave additional support for the locus. Further, the 18p locus has shown nominal evidence of linkage with psoriasis in the British population. Taken together, these ndings con rm the presence of a minor susceptibility locus for psoriasis on 18p11. Keywords: multifactorial disease/genetic mapping/ linkage analysis/skin. J Invest Dermatol 121:735 ^740, 2003 Psoriasis (OMIM#177900) is a chronic in ammatory skin disease. The disease occurs on all continents, with a peak prevalence of 2%^3% observed in North Europeans (Christophers, 2001). The skin lesions are characterized by abnormal proliferation and di erentiation of keratinocytes, angiogenesis, and mixed leukocytic in ltrate of T cells, neutrophils, and mast cells (Barker, 1991), but the exact molecular pathogenesis of psoriasis is still largely unknown. The multifactorial etiology of psoriasis is well established. Family studies show a strong genetic component in psoriasis susceptibility (Lomholt, 1963; Swanbeck et al, 1997). The concordance rate among monozygotic twins is 65%^73% compared to 15%^23% in dizygotic twins, making the estimated overall heritability about 90% (Farber et al, 1974; Brandrup et al,1978,1982). Environmental factors, however, are also needed to trigger the disease in genetically susceptible individuals (Krueger and Duvic, 1994). To nd the genes controlling susceptibility to psoriasis, several genomewide linkage studies have been published during the past 8 y. Numerous putative susceptibility loci have emerged in the scans, but the replication of the results has proved di cult, as seen also in other complex diseases (Altmuller et al, 2001). One locus, Manuscript received October 9, 2002; revised December 23, 2002; accepted for publication April 25, 2003 Reprint requests to: Professor Juha Kere, Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden. Abbreviation: NPL, nonparametric multipoint linkage analysis. however, namely PSORS1, on chromosome 6p21.3, has been replicated in several di erent populations (Nair et al, 1997; Trembath et al, 1997; Burden et al, 1998; Samuelsson et al, 1999; Lee et al, 2000; Veal et al, 2001) and can thus be considered as the major susceptibility locus for psoriasis. Other susceptibility loci that have gained a LOD score 43 in at least one study are PSORS2 at 17q25 (Tomfohrde et al, 1994; Nair et al, 1997), PSORS3 at 4q34 (Matthews et al, 1996), PSORS4 at 1q (Capon et al, 1999), PSORS5 at 3q21 (Enlund et al, 1999), PSORS6 at 19p13 (Lee et al, 2000), and PSORS7 at 1p (Veal et al, 2001). In addition to the named PSORS loci, several other suggestive susceptibility loci have also been published, for example, 16q (Nair et al, 1997) and 20p (Nair et al, 1997; Trembath et al, 1997). The signi cance of PSORS1 in the MHC region has been further established in several association studies of three tightly linked susceptibility alleles: HLA-Cw 6 (Tiilikainen et al, 1980; Enerback et al, 1997; Mallon et al, 1997), HCR WWCC (Asumalahti et al, 2000, 2002), and CDSN 5 (Ishihara et al, 1996; Allen et al,1999; Jenisch et al, 1999). Based on the association and linkage studies, the PSORS1 locus seems to explain 30%^50% of psoriasis. Other, minor susceptibility loci are thus likely to exist. The detection of the minor loci has, however, proved di cult because of locus heterogeneity, which makes the replication of the linkage di cult in di erent ethnic groups (Capon et al, 2002). The aim of this study was to search for additional psoriasis susceptibility loci in Finnish multiplex psoriasis families by a genomewide linkage approach while trying to minimize the overwhelming e ect of the PSORS1 locus. The families were rst genotyped for PSORS1 and only families who did not show linkage and association to PSORS1 were selected for the X/03/$ Copyright r 2003 by The Society for Investigative Dermatology, Inc. 735

2 736 ASUMALAHTI ET AL THE JOURNAL OF INVESTIGATIVE DERMATOLOGY genomewide scan. Our results support a locus for psoriasis susceptibility on chromosome 18p11. METHODS Patient material and selection of families We recruited 31 Finnish multiplex families with at least three psoriasis patients per family (on average 3.9 a ected per family; range, 3^10). Altogether we collected samples and data from 227 individuals of whom 121 were a ected. The sample collection was approved by the ethical review boards of all participating hospitals and the Department of Medical Genetics, University of Helsinki, and all samples were used by informed consent. The age of psoriasis onset varied between 7 and 80 y (mean, 29.6 y; median, 27.5 y), and the age at sample collection of the patients was between 12 and 89 y (mean, 46.4 y; median, 47 y). In recruiting the families, the inclusion criteria for the probands were that they were under 40 y of age and had chronic plaque psoriasis. Relatives with psoriasis were included irrespective of their age of onset or type of psoriasis; altogether 79% of all patients had plaque psoriasis. To select for PSORS1-negative families for a genome scan, all study subjects were genotyped for two SNP in the HCR gene (HCR-325 and HCR-1723) by using PCR ampli cation and altered restriction sites for AvaII and MslI, respectively, as described previously (Asumalahti et al, 2002). Based on PSORS1 status, nine families were selected for the genomewide scan. In the selected families 89% of the patients had plaque psoriasis. Genome scan The genome scan was performed using 377 uorescently labeled polymorphic microsatellite markers from a linkage mapping set (MD-10, Applied Biosystems, Foster City, CA). The average interval between the markers was 9.1 cm. The overall success rate for genotyping was 95.4%. PCR assays were performed in 5-ml volumes containing 20 ng of DNA, with reagent concentrations and temperature pro les as recommended by the reagent manufacturer (Applied Biosystems). The electrophoreses were run using Megabace 1000 capillary instruments (Molecular Dynamics, Sunnyvale, CA), and allele calling was carried out using the Genetic Pro ler 1.1 (Molecular Dynamics) software. Fine mapping To increase the marker density to 5 cm in loci with nominal evidence of linkage (3p, 11p, 12p, 15q, 18p, and 22q), we genotyped a total of 23 additional microsatellite markers. On 18p11, ne mapping was continued with 10 more markers to a density of approximately 1 cm between markers. The ne mapping markers were selected from the Genethon (ftp://ftp.genethon.fr/pub/gmap/) and Marsh eld ( eldclinic.org/genetics/) genetic maps. The order and physical distance of the markers on 18p11 were con rmed from the NCBI ( and Celera public databases ( Fluorescently labeled PCR products were run on an ABI 377 sequencer. Allele calling was carried out using Genotyper 2.0 (Applied Biosystems). Statistical analysis To analyze genomewide linkage, nonparametric multipoint linkage analysis (NPL) was performed using GeneHunter 2.1 (Kruglyak et al, 1996). No further selection or multiple testing was applied at the analysis stage, and thus our analysis constitutes a test whether there is a locus (loci) contributing to the psoriasis phenotype in these families. Association analysis on chromosome 18p was performed using the haplotype pattern mining algorithm (Toivonen et al, 2000). Haplotype pattern mining is a data-mining-based method that searches for genetic association by detecting haplotype patterns that are disease associated using a w 2 test. Haplotyping was performed in trios formed from the large pedigrees with an in-house computer program that nds a maximal number of independent trios with di erent chromosomes. A chromosome was considered as trait-associated if it occurred in any of the a ected family members and as control if it occurred only in una ected individuals. RESULTS Selection of the families for the genomewide scan To choose families for a genome scan, we rst genotyped all study subjects for two HCR SNP. PSORS1-positive individuals were de ned as those having the alleles HCR-325 Tand HCR T, and PSORS1-negative all those with other allele combinations (CG, CT, and TG, respectively). This is a conservative de nition for the PSORS1 locus, because nearly all subjects positive for these alleles are also HLA-Cw6-positive, whereas a selection of patients negative for HLA-Cw6 would still include many positive for the HCR susceptibility allele (Asumalahti et al, 2002). Based on our previous results, HCR- 325 T and HCR-1723 T are also in strong (98.3%) linkage disequilibrium with each other and with the other two SNP comprising the psoriasis susceptibility haplotype HCR WWCC (Asumalahti et al, 2002). Seventy-one percent (86 of 121) of patients and 22% (21 of 96) of una ected family members were PSORS1-positive according to our de nition. To nally select the families for the genome scan, a PSORS1- negative family was de ned as having more than two PSORS1- negative patients and at least one transmission of psoriasis from parent to o spring without cotransmission of PSORS1. Nine families (altogether 77 individuals, 37 a ected) ful lled these selection criteria and were included in the genomewide scan (Fig 1). In the selected nine families, 70% (26 of 37) of the patients were PSORS1-negative. Genomewide scan A total of ve loci showed some evidence of linkage for psoriasis (NPL score, 41.7) (Fig 2). The regions were chromosome 11p between markers D11S1338 and D11S904 (NPL score, 1.82; p ¼ 0.040), 12q between D12S364 and D12S368 (NPL score, 1.76; p ¼ 0.044), 15q between D15S1007 and D15S117 (NPL score, 1.93; p ¼ 0.034), 18p between D18S63 and D18S464 (NPL score, 1.72; p ¼ 0.046), and 22q between D22S280 and D22S423 (NPL score, 2.19; p ¼ 0.023) (Fig 2). As expected, PSORS1 at 6p showed negative NPL scores. The other known PSORS loci showed no strong evidence of linkage (NPL scores ranging from ^0.5 to 0.6) in this sample, with the exception of chromosome 3p, where a NPL score of 1.21 was observed between markers D3S1566 and D3S1278, 10 cm from the PSORS5 locus. Fine mapping We selected six loci (3p, 11p, 12q, 15q, 18p, and 22q) for ne mapping with a total of 23 microsatellite markers to increase the marker density. The NPL scores remained essentially unchanged or decreased for all the other loci but 18p. On 18p11, the NPL score increased sharply to 3.50 (p ¼ ). Next we added 9 more markers into the interval between the markers D18S63 and D18464 to increase the marker density to approximately 1 cm between markers and repeated the linkage analysis (Fig 3). The NPL score increased further to 3.58 (p ¼ ) between markers D18S63 and D18S967 (with 9 markers typed within the interval). According to the publicly available human genomic sequence, the distance between these two markers is approximately 3.2 Mb. On the other hand, genetic maps estimated the distance between the anking markers to be approximately 11 cm and showed discrepancy in the order of the markers even when the Marsh eld, Genethon, Cedar ( and decode (at map viewer maps were compared. For our analyses, we ordered the markers according to the physical map. To analyze the robustness of linkage, we used bootstrapping and calculated linkage by leaving one family at a time of the analysis. In eight of nine such analyses, the linkage remained essentially unchanged, whereas family 3 seemed to contribute the majority of the linkage information (Table I). We then reanalyzed genomewide linkage separately for this family and found that the peak at chromosome 18p is by far the strongest genetic e ect (p ¼ ), with the next best loci in chromosomes 22 (p ¼ 0.006) and 1, 5, and 6q (p¼ 0.031). Analysis of linkage by including only the markers used in a previous study with a possible linkage in the same locus (Veal et al, 2001) yielded a similarly shaped linkage result with a NPL score of 0.5 at D18S59 (data not shown). To compare the observed linkage in 14 informative families positive for PSORS1 and not included in the genome scan, we genotyped the markers D18S59, D18S471, D18S967, and D18S1150. The linkage result was negative (NPL scores from ^0.8 to ^1.6 across the interval).

3 VOL. 121, NO. 4 OCTOBER 2003 PSORIASIS SUSCEPTIBILITY LOCUS ON 18p 737 Figure 1. Pedigree structures of the nine genome scan families. DNA samples from the numbered individuals were available in the analysis. Gray, uncertain diagnosis; coded as unknown in the analyses. Black dot, PSORS1-negative individuals. Association analysis on 18p11 To explore the possibility of a shared ancestry between families, we next studied haplotype sharing between the families. All patients in families 3, 7, and 8 who showed the strongest linkage to 18p11 (NPL scores, 10.5, 2.4, and 1.9, respectively) shared the D18S471 2 allele. In addition, two of the families shared a three-marker haplotype (D18S458 2-D18S471 2-AFM238yg3 1) across the anking markers (Fig 3). We next used the haplotype pattern mining algorithm to detect the best-associated haplotype patterns. The best association was found for a three-marker haplotype (D18S AFM238yg3 1-D18S967 4) that overlapped with the haplotype shared between the largest linked families. This haplotype was found on 6 of 30 of patients chromosomes but 0 of 26 of control chromosomes (p ¼ 0.025; Fig 3). DISCUSSION PSORS1 on chromosome 6p21.3 is the only repeatedly observed locus to explain genetic susceptibility to psoriasis. Even this major locus, however, seems to explain only about 30%^50% of psoriasis cases and minor susceptibility loci are likely to exist. Indeed, at least seven candidate loci have been mapped so far. We have performed a genomewide scan in a selected set of PSORS1-negative psoriasis families from Finland to assess the role of other loci in familial psoriasis. Surprisingly, our results yielded the strongest evidence of linkage for a new susceptibility locus. A major e ect of PSORS1 was excluded by genotyping two HCR SNP (HCR-325 and HCR-1723) of the HCR WWCC susceptibility allele. The two SNP are in strong linkage disequilibrium with each other and the other two risk SNP. In our previous study of 1680 chromosomes from several populations (Asumalahti et al, 2002), the HCR WWCC allele was in very strong linkage disequilibrium also with both the HLA-Cw 6 and the CDSN 5 risk alleles. By genotyping just the two HCR SNP we could conservatively select families where PSORS1 must play a minor role. Consistent with the selection of families, PSORS1 yielded negative NPL scores in our linkage analyses (Fig 2). The PSORS1 locus has previously been shown to associate especially with familial background and early age of onset of psoriasis (Henseler and Christophers, 1985; Swanbeck et al, 1995). This was the case also in our family material: in only 3 of 31 multiplex families, there were no patients with the PSORS1 susceptibility allele. Six additional families ful lled our selection criteria for PSORS1-negative families and altogether nine families were included in the genomewide scan. After the initial selection of families, no further selection or alternative linkage models were applied. Therefore, our linkage analysis requires no adjustment for signi cance thresholds. In the genome scan, ve loci gave initial evidence of linkage in NPL (1.72^2.19) and one locus (with NPL score, 1.21) was located 10 cm from PSORS5. After increasing the marker density to 5 cm, only one locus, on 18p11.23, showed suggestive evidence of linkage (NPL score, 3.50; p ¼ ). At the other loci, NPL scores did not increase or even decreased, when the information of additional markers was added. This is expected for spurious or false peaks. A further increase of marker density to approximately 1 cm between markers yielded a NPL peak of 3.58 (p ¼ ). A bootstrapping analysis indicated that the linkage was most

4 738 ASUMALAHTI ET AL THE JOURNAL OF INVESTIGATIVE DERMATOLOGY Figure 2. Nonparametric linkage analysis results performed using GeneHunter. Solid lines, NPL curves (scale on the left y-axis); dotted lines, information content curves (scale on the right y-axis). The locations of PSORS1-7 loci are marked below curves. Dashed lines under gures, six ne mapping loci. strongly supported by one family (Fig 1, Fam 3). An analysis of PSORS1-positive families who were excluded from the genome scan yielded negative NPL scores across the 18p locus. Haplotype sharing between the linked families gave additional support for the locus. Association analysis showed evidence of association for a three-marker haplotype (D18S AFM238yg3 1-D18S967 4) just over the NPL peak. The number of independent chromosomes was quite small (30 a ected and 26 control chromosomes), and the statistical evidence for the association remained rather weak (p ¼ 0.025). All patients in the linked families, however, shared the D18S471 2 allele. In addition, two families shared a three-marker haplotype. Because the D18S471 2 allele was the major allele with a frequency of 0.54, it did not yield statistical signi cance for allele association alone. There was some discrepancy in the marker order between the di erent genetic maps on the NPL peak. The genetic distance between the markers was zero based on the sex-average maps. No recombinations were observed between the markers and thus

5 VOL. 121, NO. 4 OCTOBER 2003 PSORIASIS SUSCEPTIBILITY LOCUS ON 18p 739 Psoriasis and atopic disease share also other susceptibility regions, on 1q21, 3q21, 17q25, and 20p (Cookson et al, 2001), suggesting that genes at these loci might have general e ects on dermal in- ammation and immunity. No con rmed genes are located in the 18p susceptibility region. Several putative genes are, however, predicted in the region, and some of them are supported by EST, but no expression data are currently available. We have presented here a genomewide scan in psoriasis performed only in PSORS1-negative families. Of note, most previous genome scans have included families that have a strong contribution by the PSORS1 locus, whereas this study concentrates on families without PSORS1 e ect. Thus, the di erent genome scan results may also re ect in part PSORS1-interacting and PSORS1-independent loci. We found evidence of a susceptibility locus for psoriasis at 18p11 (NPL score, 3.6), which was further supported with a suggestive haplotype association. Together with data reported by Veal et al (2001), our ndings con- rm the presence of a minor locus for psoriasis susceptibility on chromosome 18p11. Figure 3. Nonparametric linkage analysis curve of the telomeric part of 18p (0^28 cm from telomere) after ne mapping. Fine mapping was performed in two stages. White arrowheads, markers used in the rst ne mapping; black arrowheads, markers added in the second ne mapping. Unmarked markers were used in the original genomewide scan. Black box, the haplotype pattern mining haplotype (D18S471-AFM238yg3- D18S967); gray box, shared haplotype (D18S458-D18S471-AFM238yg3). Table I. The results of leave-one-out analysis a Family left out NPL score p value a Linkage was calculated leaving one family at a time out of the analysis. the intermarker order did not a ect the overall NPL score. We ordered the markers based on the sequence data. The two overlapping haplotypes covered an approximately 700-kb region. One previous study on psoriasis sibling pairs from the British population has previously yielded nominal evidence of linkage and excess allele sharing on chromosome 18p (NPL score, 1.97; p ¼ 0.025) (Veal et al, 2001). They reported nominally signi cant p values for two markers interpreted as interesting, D18S59 (at 1.39 cm on the decode linkage map) and D18S1150 (at cm). We included the same markers used by Veal et al (2001) to our analyses for full consistency. Our linkage peak is entirely within this region of interest, with the shared three-marker haplotype spanning from D18S471 (at cm) to D18S967 (at cm). Interestingly, when we calculated linkage in our families using only the same markers as Veal et al (2001), the shape of linkage peak was similar with peak at D18S59 in both sets. Thus, the linkage results are fully consistent for location. Our report and that of Veal et al (2001) together constitute su cient evidence for a con rmed psoriasis susceptibility locus on 18p. In addition, the 18p locus has recently been reported also as a susceptibility locus for atopic disease. In the Swedish population, extreme atopic disease phenotype showed most prominent multipoint linkage to 18p (LOD score, 1.88; po0.05) (Bradley et al, 2002). We thank all the Finnish psoriasis patients and their family members for participating this study.this study was nancially supported by Sigrid Juselius Foundation, Academy of Finland, and research funds from the University Hospitals of Helsinki, Oulu, Tampere, andturku. Personal support was received from Finnish Cultural Foundation (K.A.), Paulo and the Finnish Medical Foundations (K.A, S.S.), and the Biomedicum Helsinki and the Instrumentarium Foundations (S.S.). 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