REVIEW

Genome-wide studies of psoriasis susceptibilityloci: a review

Gurdeep S. Sagoo, Michael J. Cork, Ramila Patel, Rachid Tazi-Ahnini*

Biomedical Genetics Project, Division of Genomic Medicine, D Floor Medical School,Royal Hallamshire Hospital, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK

Received 16 December 2003; received in revised form 9 February 2004; accepted 23 February 2004

1. Introduction

Psoriasis (MIM 177900) is a chronic inflammatorydermatosis affecting 2—5% of the Caucasian popula-tion [1] and 0.1—0.3% in the Far East [2] and China[3]. The characteristic skin lesion of psoriasis is ared plaque covered with silver scales. These occurmost commonly on areas such as the knees andelbows although any part of the skin may beaffected. Several clinical subtypes of psoriasis havebeen described including chronic plaque, guttate,palmar plantar pustular and generalised pustular[4]. The cutaneous manifestation of psoriasis is

also accompanied by psoriatic arthritis (PsA) in anestimated 5—36% of patients [5—8]. Psoriasis alsooccurs in 5% of patients with Crohn’s disease [9].

Psoriasis is a multifactorial disease involving theinteraction of several genes with environmentaltriggers such as streptococcal infection [10,11],stress [11], smoking [11] and physical trauma[10,11]. Lomholt [12] and Hellgren [13] undertooklarge epidemiological studies on psoriasis (in theFaroe Islands and Sweden, respectively), however,neither study revealed any clear pattern on familialinheritance. Familial studies have implicated both adominant mode of inheritance and a recessivegenetic model for psoriasis (reviewed by Lomholt[14]). It was suggested that there is a multifactorialmode of inheritance for psoriasis, and this viewhas been supported by subsequent studies

Journal of Dermatological Science (2004) 35, 171—179

KEYWORDS

Psoriasis;

Psoriatic arthritis

genome-wide scans;

Major histocompatibility

complex (MHC);

Linkage

Summary Psoriasis is a chronic inflammatory dermatosis affecting approximately0.3—5% world-wide. Since 1997, nine genome-wide scans have been published in thesearch for predisposing genes to psoriasis and psoriatic arthritis. These genome-widescans have provided results that both confirm earlier work, but which also suggestnovel regions of interest on the genome. This article reviews the results of thesegenome-wide scans, in particular two novel regions on chromosomes 3p and 15p, andcompares the study types and designs. The results in these two regions were comparedin the different studies providing no further suggestive evidence, and we suggest thatthese results may be false-positives, population-specific susceptibility loci or due tothe stratification used in the study design. We suggest stratifying the data intoepidemiological subgroups in order to make the genome-wide scans more sensitiveto loci specific to these subgroups. This approach could provide a much more powerfultechnique to study the genetics of a complex disease such as psoriasis.� 2004 Japanese Society for Investigative Dermatology. Published by Elsevier Ltd.All rights reserved.

*Corresponding author. Tel.: þ44-114-271-3785;fax: þ44-114-271-2933.

E-mail address: r.taziahnini@sheffield.ac.uk (R. Tazi-Ahnini).

0923–1811/$30.00 � 2004 Japanese Society for Investigative Dermatology. Published by Elsevier Ltd. All rights reserved.doi:10.1016/j.jdermsci.2004.02.009

[15,16]. Farber et al. [17] studied the history ofpsoriasis in affected twin pairs and found thatmonozygotic twins had a 40% concordance ratecompared to 10% for dizygotic twins. Brandrupet al. [18] calculated the heritability to be 90%,demonstrating a large genetic component for psor-iasis risk. The penetrance of psoriasis has beenestimated to be 60—75% [18—20], but these studiesrelied only on individual families with severalaffected members. The best estimation of thepenetrance comes from the major histocompatibil-ity complex (MHC) data, where an allele with 10—20% prevalence gives rise to disease with 1—2%prevalence giving the penetrance at the MHC valueof approximately 10% [21].

In psoriasis, the contribution of the differentgenetic factors varies depending upon the patientsubgroup based on the age at onset. Henseler andChristophers [20], using serological markers,demonstrated that type 1 psoriasis with age at onsetof<40 years (positive family history) was associatedwith the HLA-Cw6, while type 2 psoriasis with age atonset of >40 years (no family history) was asso-ciated with HLA-Cw2 and HLA-B27. Swanbeck et al.[10] described two peaks of age at onset for type 1psoriasis, with a large peak occurring at age of 14—19 years and a second smaller peak at an age of 45—49 years. The strongest association with HLA-Cw6was with teenage onset psoriasis (type 1).

2. Genome-wide scans

Elder et al. [22] recently reviewed the genetics ofpsoriasis, concentrating on the PSORS1 locus withinthe MHC region on the short arm of chromosome 6.They review both the evidence for the genetic basisof psoriasis and the information currently knownabout PSORS1. Capon et al. [23] have also reviewedthe MHC region and have detailed the search forPSORS1. Our paper concentrates on recent genome-wide scans that were not reviewed in detail by

either Elder et al. [22] or Capon et al. [23]. Inthe last 6 years, several genome-wide scans havebeen conducted in the search for genes predisposingto familial psoriasis and psoriatic arthritis [24—32].These studies have confirmed previous findings andalso indicate novel candidate regions. Due to thecomplex inheritance of psoriasis, the non-para-metric linkage (NPL) score method has beenstrongly favoured. Studies have generally usedthe affected sib-pair approach, although a cohortdesign using families with affected offspring wasalso used [25]. Although the affected sib-pair designis more robust to incorrect model specification(being a non-parametric method), using large pedi-grees in the cohort design has greater power totrack the linkage through a pedigree, providingthe model is correctly specified. The studiesrecruited both nuclear and extended families, withSamuelsson et al. [27] and Karason et al. [32] alsostratifying the families into groups according to thepresence of psoriatic arthritis. In the Samuelssonet al. [27] study, all individuals were examined foraches or pain localised to one or more joints.According to their criteria, 29% of individuals wereclassified as having joint complaints (possible psor-iatic arthritis). In the Karason et al. [32] study, thepatients were diagnosed with inflammatory arthri-tis, seronegativity for rheumatoid factor andunequivocal psoriatic skin lesions at the time ofdiagnosis. Asumalahti et al. [31] also stratified theirstudy by selecting PSORS1-negative families fortheir genome-wide scan. Table 1 shows the detailsof familial size and ethnic origin along with thenumber of markers used in the various studies.

Table 1 also shows that various ethnic groupshave been used. The populations are not thoughtto differ significantly from one another with theexception of Zhang et al. [30] where a Chinese Hanpopulation is used. In some of the studies, possibleethnic differences between families are not men-tioned. Table 2 shows some chromosomal regions ofinterest pooled together from the various studies.

Table 1 A summary of the family size and ethnic origin with marker details for the PS and PsA genome-wide studies

Reference No. of families Population No. of markers

Nair et al. [24] 115 American/German 287Trembath et al. [25] 61 European 260Capon et al. [26] 22 Italian 198Samuelsson et al. [27] 86 Swedish 390Lee et al. [28] 32 German 370Veal et al. [29] 158 British 271Zhang et al. [30] 61 Chinese Hans 304Asumalahti et al. [31] 9 Finnish 377Karason et al. [32] 39 Icelandic 1000

172 G.S. Sagoo et al.

Although some of the studies may have used analy-tical methods other than NPL, a constant NPL themehas been used in this review to allow a clear com-parison of scores and P-values. The GENEHUNTERprogram [33] was used in almost every study to carryout an NPL analysis (other models and programswere also used in the various studies). Karason et al.[32] carried out their analysis using the Allegroprogram [34], with Trembath et al. [25] using their

own NPL method to extract information from theirstudy data.

3. Candidate regions

Genome-wide scans have revealed linkage to sev-eral regions across the genome. The linkage hasbeen shown to be significant (p<0.01) on chromo-

Table 2 A summary of the main regions found in the PS and PsA genome-wide studies

Region Gene/locus marker Model NPL score P-value Reference

Chromosome 11p Between D1S197 and D1S2000 NPL 3.60 <0.001 Veal et al. [29]1qcen-q21 D1S305 NPL 4.07 0.0001 Capon et al. [26]1q D1S1664 NPL 4.04 0.0001 Capon et al. [26]

Chromosome 33p D3S1768 NPL 2.89 0.002 Samuelsson et al. [27]3p D3S2409 NPL 2.89 0.002 Samuelsson et al. [27]

Chromosome 44q D4S2982 NPL 2.68 0.0047 Zhang et al. [30]

Chromosome 66p21 TNFb NPL 1.57a 0.0592a Nair et al. [24]6p21 HLAC NPL 3.07 <0.001 Trembath et al. [25]6p21 TNFa NPL 6.50 <0.001 Trembath et al. [25]6p21 D6S273 NPL 5.01 <0.001 Trembath et al. [25]6p21 D6S273 NPL 4.33 <0.001 Veal et al. [29]6p21 D6S1281 NPL 2.83 0.002 Samuelsson et al. [27]6p21 D6S422 NPL 3.10 0.001 Lee et al. [28]6p21 D6S291 NPL 6.33 <0.001 Veal et al. [29]6p21 D6S1610 NPL 3.86 0.00021 Zhang et al. [30]

Chromosome 88q D8S284 NPL 2.60 0.00027 Trembath et al. [25]

Chromosome 1515p D15S817 NPL 2.96 0.0017 Samuelsson et al. [27]

Chromosome 1616q D16S3110 NPL 2.92 0.0025 Nair et al. [24]16q D16S3255 NPL 3.02 0.0018 Nair et al. [24]16q D16S3038 NPL 2.17 <0.001 Karason et al. [32]

Chromosome 1717q D17S785 NPL 2.81 0.0034 Nair et al. [24]17q D17S802 NPL 2.63 0.0056 Nair et al. [24]

Chromosome 1818p11 Between D18S63 & D18S967 NPL 3.58 0.0038 Asumalahti et al. [31]

Chromosome 1919p13 D19S916 NPL 3.50 0.0002 Lee et al. [28]19p13 D19S865 NPL 3.46 0.0003 Lee et al. [28]

Chromosome 2020p D20S851 NPL 1.55a 0.0604a Nair et al. [24]20p D20S186 NPL 2.01 0.0012 Trembath et al. [25]

a These scores from the Nair et al. [24] study are included because they provide a suggestive LOD score when using arecessive model (Table 5).

Genome-wide studies of psoriasis susceptibility loci 173

somes 6p21 [25,28—30], 1q21 [26], 1p [29], 4q [36],18p11 [31], 16q [24,32], 17q [35] and 19p13 [28].Suggestive linkage (0:01 < P < 0:05) includesregions such as chromosomes 3p [27], 4q [30], 8q[25], 15p [27] and 20p [24,25]. Chromosomal region3q21 [37] has also been shown to be of interest, butthis region has not been picked up in the genome-wide scans. Some of the candidate regions havebeen confirmed by work from independent groups,but many of them await replication. We restrictedthe use of the term ‘replicated susceptibilityregions’ to those loci in which the Lander andKruglyak [38] criteria was fulfilled. This criteriaincludes significant linkage found in an initial studyfollowed by replication in a subsequent study inwhich the pointwise P-value has reached a signifi-cance level of 0.01.

3.1. Replicated susceptibility regions

Several of the genome-wide scans have identified amajor susceptibility locus for psoriasis on chromo-some 6p21 within the MHC [24,25,27—30]. Otherstudies have also established chromosome 6p21 as aconfirmed susceptibility region [37,39,40]. Linkageof psoriasis to this region has been reviewed indetail by both Elder et al. [22] and Capon et al. [23].

Several studies have identified other non-MHCregions as being involved in psoriasis. Bhaleraoand Bowcock [41] identified a potential susceptibil-ity region in 1q21 in a study using 23 extendedfamilies. Since then, Capon et al. [26] have demon-strated significant linkage to chromosome 1q21 intheir genome-wide scan. Capon et al. [42] alsoinvestigated the interaction between the 1q21region and the HLA-C region and found significantassociation (with a P-value of 0.0043). Also onchromosome 1, Veal et al. [29] detected significantevidence for linkage at 1p with a P-value of 0.00019.

Samuelsson et al. [27] obtained an NPL score ofover 2.5 (P-value of 0.004) for marker D3S1551confirming this region on chromosome 3q21, alsoreported by Enlund et al. [43]. Chromosome 4q hasalso been identified as a susceptibility locus [30],but this locus is different from the previouslyreported locus (PSORS3) on chromosome 4q [36].Nair et al. [24], Samuelsson et al. [27] and Enlundet al. [37] have all found evidence to confirm earlierwork by Tomfohrde et al. [35] confirming chromo-some 17q25 as another region of interest. Helmset al. [44] have also recently shown a disease-associated SNP which leads to loss of the RUNX1binding site at SLC9A3R1, a member of N-acetyl-transferase family, as a susceptibility factor forpsoriasis on chromosome 17q25. Lee et al. [28]and Veal et al. [29] both provided evidence for a

susceptibility locus on chromosome 19p13. Morerecently, Hensen et al. [45] have provided evidencefor the possibility of both susceptibility and protec-tive loci residing within this 19p13 region. Chromo-some 20p has been implicated by both Nair et al.[24] and Trembath et al. [25] (D20S186, P-value of0.0012; D20S851, P-value of 0.00026, respectively).

3.2. Potential susceptibility regions

Nair et al. [24] and Trembath et al. [25] studies alsoprovide evidence for potential susceptibility regionson 16q and 8q, respectively. Evidence for furtherpotential susceptibility loci is provided by Asuma-lahti et al. [31] for 18p11 when selecting familiesthat are PSORS1-negative and Matthews et al. [36]for 4q. Karason et al. [32] provide evidence forlinkage to PsA on chromosome 16q with a LOD scoreof 2.17. When using only paternal transmission toaffected individuals a maximum LOD score of 4.19at marker D16S267 is reported. As can be seen fromTable 2, Samuelsson et al. [27] has found evidenceof linkage in two novel regions on chromosomes 3p(marker D3S1768, P-value of 0.002) and 15p (markerD15S817, P-value of 0.0017). Other studies havepublished no or very little data regarding theseregions as a psoriasis susceptibility region. TheSamuelsson et al. [27] study was conducted witha Swedish population that was stratified into thosefamilies with joint complaints and those familieswithout joint complaints. When all of their datawere analysed together, neither region gives a sig-nificant NPL score. It is possible that these aregenuine results because of the interaction of psor-iasis with the joint problems, although neitherregion was highlighted by the Karason et al. [32]study which stratified for psoriatic arthritis. Thisstudy was the only one to stratify for this problem,and this may be the reason why no other study hasfound any supporting evidence. To follow up thesetwo regions (chromosomes 3p and 15p) a request forfull data including unpublished results was made,and we were able to gain full access to the unpub-lished results for Nair et al. [24].

Nair et al. [24] study shows no significant evi-dence for linkage of psoriasis to either the 3p or 15pchromosomal regions, although both of theseregions were suggested by the Samuelsson et al.[27]. It is interesting to note that in the 3p region, asyou move along the markers (D3S1259, D3S1293,D3S1619) in the Nair et al. [24] analysis on thechromosome towards the marker of interest(D3S1768) in the Samuelsson et al. [27] analysison the NPL scores show an clear increase in score(Table 3). The closest marker in the Nair et al. [24]analysis is D3S1619, located 3.6 kcM towards the

174 G.S. Sagoo et al.

telomere from the D3S1768 marker used bySamuelsson et al. [27].

Table 4 compares the 15p chromosomal region inboth the Nair et al. [24] and Samuelsson et al. [27]studies. The D15S817 marker showing suggestiveevidence in Samuelsson et al. [27] is very telomeric,and the closest marker (D15S122) used by Nair et al.[24] is 6.3 cM towards the centromere. None of thethree markers used by Nair et al. [24] provides anysuggestive evidence, and unlike the chromosome3p region there is no obvious pattern shown by theNPL scores.

3.3. Potential susceptibility regions under arecessive gene model

In Table 2, NPL scores from Nair et al. [24] forchromosomal regions 6p21, 16q and 20p, usingmarkers TNFB, D16S3110 and D20S851, respec-tively, were included in the comparison of NPLscores despite two of the three markers (TNFBand D20S851) yielding non-suggestive scores.Table 5 compares the scores generated by Nairet al. [24] at the same markers using an NPL methodand a recessive model. It is interesting to note thatTNFB and D20S851 yield suggestive LOD scoresunder a recessive model but are no longer sugges-tive when using an NPL method. It is well known thatparametric models have greater power than NPLmethods when the correct model is specified, andthis may be the case here for these regions. At the

marker on chromosome 16 (D16S3110), both para-metric and NPL scores are of interest. When using adominant model for all regions Nair et al. [24] didnot find any result that was statistically signifi-cance.

3.4. Incomplete data

In the remaining genome-wide studies [25,26,28—30] nothing suggestive has been found in chromo-somal regions 3p and 15p. The ‘missing data’ inthese two regions is probably due to publicationbias as only the most significant results are pub-lished, and thus it may be safe to assume thatnothing of significance was found in these regions.

Table 3 The chromosomal 3p region

Region Locus/marker

Distance fromtelomere (kcM)a

NPL score P-value Reference

Chromosome 33p D3S1259 30.9 0.73 0.2287 Nair et al. [24]3p D3S1293 36.9 1.46 0.0727 Nair et al. [24]3p D3S1619 55.4 1.86 0.0334 Nair et al. [24]3p D3S1768 59 2.89 0.002 Samuelsson et al. [27]3p D3S1581 67.7 0.54 0.2887 Nair et al. [24]

a Distances and orders are arranged according to the final Genethon human linkage map [57].

Table 4 The chromosomal 15p region

Region Locus/marker

Distance fromtelomere (kcM)a

NPL score P-value Reference

Chromosome 1515p D15S817 0 2.96 0.0017 Samuelsson et al. [27]15p D15S122 6.3 0.94 0.1249 Nair et al. [24]15p D15S165 20.2 1.04 0.1066 Nair et al. [24]15p D15S118 32.2 0.50 0.2358 Nair et al. [24]

a Distances and orders are arranged according to the final Genethon human linkage map [57].

Table 5 Same markers but different models: by Nairet al. [24]

Region Gene/locusmarker

Model LODscore

P-value

Chromosome 66p21 TNFB Recessive 2.585 0.00028

NPL 1.57 0.0592

Chromosome 1616q D16S3110 Recessive 2.504 0.00034

NPL 2.92 0.0025

Chromosome 2020p D20S851 Recessive 2.619 0.00026

NPL 1.55 0.0604

Genome-wide studies of psoriasis susceptibility loci 175

Thus, these regions are either false-positives, orthey may just be isolated to the Swedish populationthat was used in the Samuelsson et al. [27] study.The family sizes for all the studies gave large num-bers of affected individuals and the number ofmarkers used was 200—400 in each genome scanexcept for Karason et al. [32], with average markerspacing of 10—14 cM. In terms of methods of ana-lysis used, the authors generally relied on NPLmethods using the GENEHUNTER [33] package tocalculate NPL scores. Trembath et al. [25] usedtheir own novel NPL method to extract full informa-tion from the data. Various other methods such asparametric models and packages including LINKAGE[46] and Allegro [34] were also used.

4. Discussion

In the past 7 years, nine genome-wide studies havebeen conducted to identify major susceptibility locifor psoriasis and psoriatic arthritis. The genome-wide scans reviewed here provide confirmation ofprevious work and highlight the existence of poten-tially new regions of interest. Almost all the gen-ome-wide scans performed to date showedsignificant LOD scores in the MHC region. Caponet al. [26] and Karason et al. [32] showed no sig-nificant linkage to the MHC region at markerD6S273. However, Capon et al. [42] did show linkageto the MHC region under the assumption of itsinteraction with the 1q21 region. The Caponet al. study [26] provided further evidence forthe inclusion of chromosome 1q21 as a potentialsusceptibility region as initially identified by Bha-lerao and Bowcock in their study of 23 extendedfamilies [41]. Asumalahti et al. [31] used familiesnot associated with PSORS1 (MHC) in their genome-wide scan.

It is estimated that PSORS1 accounts for approxi-mately 33% of the genetics of psoriasis in the Cau-casian population [25]. With this region also showingsignificant linkage in the study carried out by Zhanget al. [30] in the Chinese Hans population, it may bethat this locus is a major factor not just in theCaucasian population. The susceptibility region ofPSORS1 has been refined to approximately 200 kbwithin the MHC starting 60 kb telomeric to HLA-C[39,47]. This interval contains several gene candi-dates including corneodesmosin (CDSN) [48—50] andPg8/helix coiled coil rod homolog (HCR) [51], whichshow a strong association with psoriasis. Conver-sely, TCF19, which is approximately 5 kb centro-meric to Pg8/HCR, failed to show any associationwith psoriasis [52]. Three other genes are locatedwithin the candidate region (telomeric to HCR),

small proline rich (SPR1) and SEEK1 locatedbetween the CDSN and HCR and STG 2.5 kb telo-meric to the CDSN [45]. SEEK1 has been recentlyshown to be associated with psoriasis independentlyof HLA-Cw�0602 [53]. Recently, a large collabora-tive approach was adopted by the InternationalPsoriasis Genetics Consortium [54] in order to assessthe linkage to 14 candidate susceptibility loci in acohort of 942 affected sib-pairs. This study providedfurther support for the major role of the MHC butprovided no compelling support for non-MHC loci.The strongest evidence for non-MHC loci were pro-vided by regions on chromosomes 10q and 16q, tworegions previously reported by the Nair et al. [24]study.

Using the transmission disequilibrium test (TDT)in families we have recently shown that there arehigh-risk haplotypes (HRH) containing 49 SNPswithin 46 kb containing HCR, SPR1, SEEK1, CDSNand STG (RTA, unpublished). Veal et al. [41] alsorecently found in a family based study using markersalong 150 around HLA-C that the strongest associa-tion was with two SNPs (nos. 7 and 9) at 4 and 7 kbcentromeric to HLA-C, respectively, confirming pre-vious findings by the same group [55]. In the samestudy, Veal et al. [41] showed a strong association tothe region telomeric to HLA-C around the 46 kbregion harbouring PSORS1 in both Caucasian andJapanese psoriatic populations [39,47]. The pre-sence of strong association around HLA-C and113 kb telomeric to HLA-C with weak associationbetween these intervals suggest that there may betwo loci PSORS1a around HLA-C and PSORS1b withina group of genes called the MHC-epidermal genecluster (MHC-EGC) [56] spanning a 46 kb interval(Fig. 1). Another explanation is that the non-asso-ciated chromosome region is newly generated,post-dating the appearance of the ancestral MHCsusceptibility haplotype. Also, there may be regionswhere very common non-disease haplotypes such asCw7-B8 happen to carry the same chromosomalregion, making it look like there are two peaks.

The MHC is the only region which has been con-sistently implicated and successfully replicated inpsoriasis, we believe that the increase in effect ofthe MHC locus in psoriasis in the Caucasian popula-tion could be due to strong linkage disequilibriumwith HLA alleles which are under positive selection[58]. There is a direct link between the frequency ofMHC markers in the population and the prevalenceof psoriasis in the same population. Prevalence ofpsoriasis varies significantly with ethnicity, beingvery high in Northern Europe and Russia (2—5%) andvery low in the Far East and China (0.1—0.3%). Thefrequency of Cw6 is also in keeping with the ethnicalvariation of psoriasis prevalence. In populations

176 G.S. Sagoo et al.

with a European origin, Cw6 is relatively frequent(0.10), however, the frequency of Cw6 is very low inChina and Japan 0.06 and 0.01, respectively [59].The EH57.1 ancestral haplotype which containsDRB1�0701, DQA1�0201, DQB1�03032, B13/37 andCw6 is a susceptibility locus in both populations.However, recent data from Hui et al. [60] has shownthat the CDSN polymorphisms associated with psor-iasis in the Caucasian population are not associatedwith the disease in the Japanese population, sug-gesting that a different MHC risk haplotype is asso-ciated with psoriasis in the Japanese population.

The results of these genome scans, althoughhighlighting regions of potential interest, may bedifficult to reproduce. This may be due to false-positive results, population-specific susceptibilityloci or stratification used in the study design. It willbe necessary to confirm some of the novel regionssuch as those found by Samuelsson et al. [27] byusing different samples from the same population toallow for the stratification of families and possibleethnic differences. As genome-wide studies are

becoming more frequently used, the study designand analysis issues are becoming clearer. It is pos-sible that the discordance of genome-wide scansmay be due to both stratification within the popula-tion and also epidemiological stratification of thepatients within the families. The different epide-miological subtypes of psoriasis based on patientage at onset of disease have been associated withdifferent genetic loci on chromosomes 2 and 6[20,48,60]. However, none of the genome-widescans have defined index cases or other familymembers according to subtypes. It is likely that inthese studies that the majority of families would beof type 1 psoriasis. However, contrary to the origi-nal definition of type 2 psoriasis some individuals inthis group also have a positive family history ofpsoriasis. The segregation of psoriasis accordingto patient age at onset subgroups has also not beenstudied in families.

It could be informative to reanalyse the genome-wide data after subdivision into the different epi-demiological subgroups (such as type 1 or 2 psor-

Fig. 1 The MHC region of interest. Although several studies have found strong association to psoriasis to the regioncentromeric to HLA-C, strong association has also been found telomeric of HLA-C in an overlapping region containingthe psoriasis risk haplotype (PRH) used in our own study (RTA, unpublished data).

Genome-wide studies of psoriasis susceptibility loci 177

iasis). Very large family numbers would be requiredwhich could be achieved by a large-scale meta-analysis of the genome-wide scans [61]. By stratify-ing the data into epidemiological subgroups thescans could become more sensitive since taking amixture of disease subgroups will dilute true resultsif they are specific to these subgroups. This couldprovide a much more powerful technique to studythe genetics of a complex disease such as psoriasis.

Acknowledgements

We thank James Elder and Rajan Nair for allowingaccess to the full results of their genome scan [24].The financial support for this work was provided by aUniversity of Sheffield Studentship. RTA and MJChave received support from the Psoriasis Associa-tion UK and the Cecil King Memorial Foundation.

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