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
Identification of a major susceptibility locus on chromosome 6p and evidence for further disease loci revealed by a two stage genome-wide search in psoriasisRichard C. Trembath1,*, R. Lee Clough1, Jane L. Rosbotham1,2, Andrew B. Jones2, Richard D. R. Camp1, Angela Frodsham1, Julie Browne1, Ruth Barber1, Joseph Terwilliger3,4, G. Mark Lathrop3 and Jonathan N. W. N. Barker2
1Departments of Genetics and Medicine and Therapeutics, University of Leicester, Leicester LE1 7RH, UK, 2St. John's Institute of Dermatology, UMDS St. Thomas' Hospital, London SE1 7EH, UK, 3Wellcome Trust Centre for Human Genetics, University of Oxford, Windmill Road, Oxford OX3 7BN, UK and 4Columbia University Department of Genetics and Development and Department of Psychiatry, 722 West 168th Street, New York, NY 10032, USA
Received January 2, 1997;Revised and Accepted February 19, 1997
Psoriasis is a common chronic inflammatory disorder of the skin. To further understand the pathogenesis of psoriasis we have chosen to investigate the molecular genetic basis of the disorder. We have used a two-stage approach to search the human genome for the location of genes conferring susceptibility to psoriasis, using a total of 106 affected sibling pairs identified from 68 independent families. As over a third of the extended kindreds included affected relatives besides siblings, in addition to an analysis of allele sharing between affected sibling pairs, a novel linkage strategy was applied that extracts full non-parametric information. Four principal regions of possible linkage were identified on chromosomes 2, 8, 20 (p <0.005) and markers from the MHC region at 6p21 (p <0.0000006) for which significant evidence of linkage disequilibrium was also observed (p <0.00002). Whilst data from limited case control associations exist to implicate the MHC, the results of this genome wide analysis demonstrate that, at least in the population studied, a gene or genes located within the MHC and close to the class 1 HLA loci, represent the major determinant of the genetic basis of psoriasis.
Psoriasis vulgaris is characterised by the appearance of multiple red, scaly, indurated plaques. The disease is common affecting 2% of the UK population and is found in all racial groups (1 ). Although the disease is rarely fatal, objective measurements indicate that with more severe disease, psoriasis has a significant adverse effect on the quality of life (2 ). The impact for health care of psoriasis is considerable. In the USA the annual expenditure has been estimated to exceed $1.6 billion per year. All topical and systemic treatments for psoriasis are symptomatic, none leads to a cure and all are associated with potentially serious side effects.
The causes of psoriasis are unknown (3 ,4 ). Epidemiological studies, including concordance rates in twin pairs and siblings, strongly implicate genetic factors in the pathogenesis of psoriasis (5 ). The risk to siblings of an affected individual of developing psoriasis is four-fold that observed in the general population (1 ). Occasionally multigeneration kindreds with psoriasis are observed. In one such large extended white American family anonymous microsatellite markers at 17q demonstrated linkage to psoriasis under an assumed autosomal dominant model of inheritance (6 ). Studies in extended kindreds from Northern Europe have failed to confirm linkage to the long arm of chromosome 17 and suggest that a susceptibility locus in this region is unlikely to account for a significant proportion of the genetic contribution to psoriasis (Burden et al., manuscript in preparation) (7 ,8 ). Recently a further locus at 4q (D4S1535, Zmax = 3.03, [theta] = 0.08) has been proposed through the analysis of extended families from Ireland and the UK (9 ). The authors of both these reports suggest caution in the assessment of linkage to psoriasis susceptibility loci as a number of factors complicate the analyses. These include incomplete penetrance, phenocopies, misdiagnosis and the lack of a robust genetic model that accurately accounts for the observed familial aggregation, which all serve to compound parametric linkage studies of common disorders with non-Mendelian inheritance such as psoriasis.
Several investigators have conducted case control association studies in psoriasis typically concentrating upon genes involved in the regulation of the immune response (10 ,11 ) and particularly the major histocompatibility complex [human leucocyte antigen (HLA) region] on the short arm of chromosome 6 (12 ,13 ). Of the many case control studies performed, associations with psoriasis have been identified for multiple class I and class II MHC antigens including HLA- B13, B17, B39, B57, Cw6, Cw7, DR4 and DR7 and are likely to reflect extended linkage disequilibrium across the region (14 ). The strongest association appears to be with the class I antigen HLA-Cw6 which, in some series, is seen in up to 80% of patients compared to 10% in the general population. There are, however, several factors which make interpretation of these data problematic including patient ascertainment bias, control population characteristics, small sample size and reliance on serologically defined class I antigens. Furthermore, studies performed in small numbers of families have failed to demonstrate linkage to the MHC (15 ,16 ). Hence the molecular genetic basis for these associations remains unclear.
As the number of genes involved in the pathogenesis of psoriasis and their chromosomal location are presently unknown, we have performed two stage (17 ) systematic genome wide genotyping in a large cohort of nuclear psoriatic families and sibling pairs and analysed the data by including a novel method designed to extract full non-parametric data from all affected relatives.
The primary study group consisted of a total of 254 individuals recruited in Britain. The mapping panel consisted of 66 pairs of affected siblings from 41 families, with extended relationships as described in Table 1 . In 94% of the affected cohort, chronic plaque type psoriasis was the presenting form. The other forms observed within the extended families were guttate psoriasis (3%) and palmoplantar psoriasis (3%). The group was genotyped at a total of 260 autosomal microsatellite markers.
For each marker, a non-parametric statistical estimate of linkage was calculated for affected siblings with psoriasis (Fig. 1 ). Nominal evidence for linkage was defined at the level of p <= 0.01. Using these criteria, linkage was identified at 10 markers (7.8%), distributed over eight chromosomes; on chromosome 2 (D2S134), chromosome 6 (three adjacent markers, D6S276, D6S273 and TNF[alpha], which span an interval of 1.5 centiMorgans and include the major histocompatibility region), chromosome 8 (D8S284), chromosome 11 (D11S910), chromosome 12 (D12S99), chromosome 14 (D14S50), chromosome 16 (D16S422) and chromosome 20 (D20S186).
For three distinct chromosomal regions two adjacent markers from the mapping panel reached a p value of p <= 0.1; D4S418 and D4S405 separated by 10 cM on chromosome 4p, D14S72 and D14S50 with a marker interval of 5 cM and D16S289 which lies within 9 cM from the marker D16S422 at chromosome 16q. We found no evidence for distortion of allele sharing for either markers D17S784 (p = 0.5) or D4S408, both of which map within the linkage intervals previously reported for psoriasis susceptibility loci (6 ,9 ).
Details of the two psoriasis family panels used for linkage analysis.
Number of affected relations and families
MULTIPLEX
ASP1
2 sibs
20
22
3 sibs
8
6
4 sibs
2
-
5 sibs
1
-
Total affected sib pairs
66
40
Total affected relative pairs (non-sib)
15
3
Total independent families
41
27
In the MULTIPLEX panel, 21 affected sibships had both parents, eight had one parent and two had neither parent available for genotyping. In the ASP1 panel, the corresponding number of parents available for genotyping were 21, 4 and 3. In the statistical analyses dependence of multiple affected sibling pairs was taken into account as previously described (22,23). In 13 and one of the MULTIPLEX and ASP1 families respectively, affected relatives existed in two or more generations.
Results of full non-parametric (association and affected relative) analysis performed on the combined family cohorts (MULTIPLEX and ASP1)
Marker
Heterogeneity
Within sibpairs p-value
Between sibpairs p-value
All linkages p-value
All linkages LOD score
Combined linkage and associationa p-value
D6S422
0.74
0.0043
0.064
0.005
2.19
D6S299
0.79
0.00044
0.144
0.001
2.91
D6S276
0.74
0.0097
0.42
0.032
0.90
D6S265
0.78
0.0011
0.097
0.002
2.64
HLA-C
0.82
0.00016
0.02
0.00041
3.07
0.0000004
TNF[alpha]
0.76
0.00000052
0.032
0.00000058
6.5
n.d.
D6S273
0.75
0.00027
0.0013
0.000014
5.01
0.000003
D6S426
0.85
0.025
0.012
0.006
2.13
aData presented for markers with evidence of allelic association only.n.d., Allelic association at TNF[alpha] not assessed as fluorescence based typing did not allow unambiguous calling of alleles.
Proportion of zero, one or two alleles shared common by descent by affected siblings for the three chromosome 6p21 markers showing strongest evidence for linkage in the combined datasets of MULTIPLEX and ASP1
Analysis of the eight chromosomal regions suggestive of linkage was extended in a second independent panel of 40 siblings (ASP1) affected with psoriasis (all with chronic plaque type psoriasis) recruited within the UK. From the marker mapping set, two adjacent markers located at chromosome 6p21 each showed evidence of linkage with psoriasis in the second sample of siblings: D6S273 (p <0.03) and TNF[alpha] (p <0.001). Additional markers adjacent to and within the intervening linkage interval and including the MHC locus HLA-C were then studied in the combined cohort of affected siblings and multiplex families. As 15 (33%) of the families in MULTIPLEX had either multiple affected generations and/or multiple affected relative pairs other than sibs we analysed the data by a novel approach to extract all non-parametric linkage information, to include a search for allelic association (see Materials and Methods). Significant evidence of linkage was observed in the extended data set for the consecutive markers D6S273 (p = 0.000014) and TNF[alpha] (p = 0.00000058). The gene encoding the class I molecule HLA-C which lies within 2 Mb of the markers displaying linkage, was genotyped using molecular methods and also gave support for linkage at p = 0.00015. Evidence for allelic association was observed for alleles at two of the three linked loci; allele 5 (136 mobility units) at D6S273, p = 0.0074 and a total of 62 HLA-Cw6 alleles were transmitted from parents to an affected offspring compared to 22 not transmitted (p = 0.00002). The results of the combined analysis of all independent nonparametric data for the chromosome 6p21 markers are presented in Table 2 and the proportion of alleles shared by common descent for the three most closely linked markers in Table 3 .
The most compelling evidence in favour of linkage to non-MHC loci was identified at three chromosomal regions: chromosome 2 (D2S134; p = 0.0077, LOD score = 1.27), chromosome 8 (D8S284; p = 0.00027, LOD score = 2.60 ) and chromosome 20 (D20S186; p = 0.0012, LOD score = 2.01). Results are presented in Table 4 for these markers in the individual data sets (MULTIPLEX and ASP1) and the combined sets. No allele at any of these three loci showed evidence of allelic association. Support for linkage was not observed for any flanking marker from the mapping panel at these three loci, although the intermarker distances were large; D2S177-19 cM-D2S134-14 cM-D2S139, D8S198-12 cM-D8S284-13 cM-D8S272, tel-D20S186-9 cM-D20S112-8 cM-D20S200. The remaining four markers, D11S910, D12S99, D14S50 and D16S422 all showed reduced evidence for linkage in the second cohort of affected siblings and consequently in the combined data set.
Significance of linkage tests (shown as p-values) for markers characterised in the two family panels, MULTIPLEX and ASP1
Marker
MULTIPLEX p-value
ASP1 p-value
Combined p-value
D2S134
0.0055
0.23
0.0077
D8S284
0.00079
0.049
0.00027
D20S186
0.0082
0.026
0.0011
Mean IBD (identity by descent) estimates on the combined datasets of 106 sibling pairs with psoriasis are given for the markers with the strongest evidence for linkage.
These results provide significant evidence for the presence of a psoriasis susceptibility locus within the MHC region on chromosome 6p21. The contribution of a single locus to the familial clustering of a disease, termed [lambda]s, may be estimated by calculating the ratio of the expected and observed proportions of affected sibling pairs who share zero alleles identical by descent (IBD) (18 ). An overall estimate of sibling recurrence risk for psoriasis is 4.0 (19 ) and using estimates for affected IBD allele sharing from the combined analysis for the class 1 molecule HLA C, [lambda]s 1 = 1.4 indicating that the contribution of this locus to the relative risk of developing psoriasis is ~35%. MHC Class 1 genes have previously been implicated in disease susceptibility in psoriasis using case-control disease association studies (20 ). However a number of limitations apply to many of these reports and include small numbers of subjects studied, difficulties of rigid genetic population stratification and the use of insensitive methods to assign class 1 MHC genotypes. We used a molecular method, sequence specific oligonucleotide priming (SSOP), to detect HLA-C alleles (21 ) as a significant number are not detected (null alleles) by widely used serological assays. Linkage was detected using robust non-parametric methods in a cohort of over 100 affected sibling pairs with additional linkage information obtained from other affected relatives. Allelic association was sought by a genotype-based haplotype relative risk approach that compares genotypes in an affected individual with the two parental alleles that were not transmitted to the affected offspring.
A total of 61 European Caucasoid families with a minimum of two affected members with psoriasis were initially identified by co-operating dermatologists (60%), through the Psoriasis Association of Great Britain (15%) and national press advertisement (25%). All affected individuals and their relatives were assessed by a single dermatologist (JLR). A diagnosis of psoriasis was made using standard clinical criteria as described elsewhere (1 ). In this and the ASP1 panel, the diagnosis of psoriasis was verified in a sample of affected individuals (15%) by an experienced dermatologist (JNWNB). Concordance of the diagnosis was 100%. All probands had chronic plaque type psoriasis. In a total of 26 (12.3%) individuals with suggestive skin lesions, including skin disease confined to flexural sites, the diagnosis of psoriasis could not be confirmed. These individuals were therefore considered as of unknown phenotype and either genotyped to aid likelihood estimates for allele sharing when parents were missing, or if only singleton affecteds remained, the family was not included in the study. A primary panel of 41 multiplex families (MULTIPLEX) comprising a total of 262 individuals with 66 affected sibling pairs were used for the whole genome analysis. The mean age of onset in this group of 135 affected individuals [60 male (44.4%) and 75 female (55.6%)] was 16.8 (range 1-59) years.
An independent panel (ASP1) was recruited to allow further evaluation of the results of the primary genome mapping data and ascertained from similar sources using identical clinical criteria (1 ). These kindreds were assessed by a single research nurse with 4 years experience in dermatology (AJ), and comprised 28 families with a total of 40 affected siblings [25 male (41%) and 36 female (59%)] all present in single generations. The mean age of onset of psoriasis in the ASP1 panel was aged 14.6 (range 3-45) years. DNA was extracted from peripheral venous blood from all affected family members and willing first degree relatives and stored at -70oC until genotyped.Approval of this study was provided by the Guy's and St. Thomas' Hospitals Ethics Committees.
Genotyping was performed for 260 highly polymorphic microsatellite markers spanning the 22 autosomes as previous described (27 ). For further details of markers used in the study, e-mail rtrembat@hgmp.mrc.ac.uk. Using data from the Genethon human linkage map (28 ), the spacing between adjacent markers was estimated to be 14.1 cM. For a total of 66 markers the interval was greater than 14 cM with the greatest being 38 cM between D1S107 and D1S252, hence a total of 97.1% of the genome lies within 20 cM of a marker and the mean heterozygosity of markers used was 78.9%.
Genotypes at each marker were determined using fluorescence-labelled primers and semi-automated techniques, as described previously (22 ). Briefly, conditions for PCR were optimised for each primer pair over a range of annealing temperatures (53-61oC) and magnesium concentrations (1.0-2.5 mM MgCl2). Amplifications were performed in 96-well microtitre plates (Costar) on MJ Research machines (PTC 225). Each 15 [mu]l PCR mixture contained 50 ng DNA, 0.2 U Taq polymerase, 40 ng of each primer, 1.5 [mu]l 10* potassium chloride buffer and magnesium chloride in distilled water. Pooled amplified DNA was electrophoresed on 6% acrylamide gels, which were run for 4.5 h at 900V using model 373A automated sequencer (Applied Biosystems). Semi-automated DNA fragment sizing was performed using GENESCANTM 672 (version 1.1) software, and genotyping carried out using GENOTYPERTM version 1.1 software (Applied Biosystems). HLA-C genotypes were determined by locus-specific amplification of the polymorphic sequences that encode the peptide-binding [alpha]1 and [alpha]2 domains of the class 1 protein (28 ). Alleles were detected using 26 sequence specific oligonucleotide probes as these DNA based methods have been shown to detect all common heterozygous individuals (21 ) detecting alleles beyond the resolution of presently available serological methods.
Full nonparametric analysis. The data were analyzed with a novel nonparametric analysis method which partitions the overall evidence of linkage into three components: (a) linkage within sibships; (b) linkage between sibships; (c) association between pedigrees (i.e. linkage within populations-between pedigrees).(a) Linkage within sibships
Initially, extended pedigrees were divided into component nuclear pedigrees and affected sib-pair analysis was undertaken with the method described by Satsangi et al. (22 ) which is essentially equivalent to the LOD score calculated under the assumption of a simple recessive disease model with phase-unknown matings. Briefly, the likelihood contribution for meioses from a heterozygous parent with n affected offspring, of which m inherited one marker allele and n - m the other, is [[rho] m (1 - [rho])n - m + [rho]n - m (1 - [rho])m], and for the whole family the contribution is the product of the two parental contributions. If parental contributions are missing, the likelihood is a sum of terms corresponding to each of the possible parental genotype combinations, weighted by the genotype frequencies calculated under the assumption of Hardy-Weinburg equilibrium and incorporating information on all offspring (assuming Mendelian segregation for unaffected offspring). The likelihood ratio test statistic, 2ln[L([rho])/L([rho] = 0.5)] has been shown in sharp contrast to traditional sibpair methods, to have a null hypothesis distribution that is almost perfectly a 50-50 mixture of a point mass at 0, and a [chi]2 distribution (22 ,23 ). The likelihood computed for each value of [rho] [denoted L - WS ([rho])] comprises the first element of the combined test statistic.(b) Linkage between sibships within pedigrees
In contrast to the situation for sibpairs, in the absence of consanguinity more distantly related individuals can share at most one allele IBD at the trait locus from a single common ancestor. Linkage analysis of such data should be nearly equivalent to considering the pedigree likelihood under a dominant mode of inheritance. To implement a non-parametric statistic, we first trimmed the extended pedigrees of all unaffected persons with no affected descendants (as they contain no information about IBD among the affected individuals in the pedigree). Then for any siblings left, they are further truncated such that one and only one affected sibling per sibship is included in the analysis; the affected sib is selected at random from the sibship. If there are multiple sibs each of whom has an affected descendant, then they are all included (of necessity) in this information twice in the joint analysis. What is left is a minimal set of affected, connecting and married-in individuals. The analysis is undertaken assuming a two-allele trait locus with genotypes 1/2 for all affected and connecting individuals, 1/1 for all married-in, unaffected individuals and unknown phenotype who could have transmitted the disease. The frequency of this `2' allele is set infinitesimally small such that only one of these parents is likely to carry the trait allele. Similarly, all individuals who have parents in the pedigree, and affected descendants are given trait locus genotype 1/2, since if the affecteds received the trait allele IBD this is necessarily the genotype of each intermediate individual. Analogous with the above, the likelihood, taking account of the marker locus is written as a function of [mu] where [mu] is equivalent to the recombination fraction under the simple dominant model. The likelihood ratios [denoted L - BS ([mu])] comprises the second element of our combined test statistic. The distribution of the likelihood ratio statistic itself, 2ln [L - BS ([mu])/L - BS ([mu]= 0.5)] is also a 50-50 mixture of point mass at 0 and [chi]2.(c) Allelic association between pedigrees
The final component of the test statistic measures the association of the marker and the trait loci which could either be due to linkage disequilibrium or a direct aetiological relationship between the marker and disease. A haplotype relative risk approach has been adopted in which one affected individual per pedigree is ascertained to determine case/control alleles. The selection criteria are: (i) first look for trios of an affected offspring with both parents all typed at the marker locus. If within a single pedigree a set of such trios is found, one is randomly chosen for inclusion in the analysis, the genotype of the affected offspring is used as the case sample genotype from this pedigree, and the control sample genotype is obtained from the two alleles which were not transmitted to this child from his parents. (Note that heterozygous and homozygous parents are both used, as this is more powerful in an association test than discarding the homozygotes as in the TDT linkage test). If no such trio is found in a pedigree, an affected offspring who is genotyped and has at least one parent genotyped is selected; in this case there would be two transmitted alleles identified and only one non-transmitted allele in the study. As a last resort, an affected individual with no genotyped parents is selected to contribute two alleles to the case sample in lieu of discarding all information in the pedigree. The likelihood is computed following the method of Terwilliger (1995) (30 ) as a function of [lambda], the percentage of the total possible association which is observed in this sample (i.e. it is on a scale between 0 and 1 with 0 meaning no association and 1 meaning complete association). The likelihood thus computed is then denoted L - LD([lambda]). The distribution of the statistic, 2ln [L - LD([lambda])/L - LD ([lambda]=0)] is unfortunately very complicated, but assuming a 50-50 mixture of [chi]2 and point mass at 0 is very conservative and yet very powerful. In reality the point mass at zero can be as large as 80-90% for some markers under the null hypothesis (31 ).(d) Overall evidence of linkage and association
To ensure a conservative overall test statistic, each of the three likelihoods was maximised independently over their respective parameters. The overall likelihood test is then L - Linkage = [maxL - WS ([theta])] maxL - BS([theta])/L - WS ([theta] = 0.5) L - BS ([theta] =0.5), and the overall likelihood test for linkage and association together is just L- complete = [L-Linkage)(maxL - LD([lambda])]L - LD([lambda] = 0). The distribution of these likelihood statistics is derived from the independent distributions of their independent components, and p-values are thus derived. Note that this is less than optimally powerful, since if there is linkage there is some relationship between the [theta]s from the within and between sibpairs analyses, and taking advantage of this relationship may be more powerful. This has not been exploited in this study as even this more conservative approach was very significant in this set of data for psoriasis.
G. Mark Lathrop is a Wellcome Trust Principal Fellow. Joseph D. Terwilliger is supported by a Hitchings-Elion Fellowship from the Burroughs Wellcome Fund and by a NIH grant (HG000008). We thank Susan Daniels for help with computer programmes and Dr K. Welsh for advice on HLA C typing. The financial support of the Psoriasis Association of Great Britain and Henry Smith Charity (RCT, RDC and JNWNB) the Dunhill Medical Trust (JNWNB) and the Wellcome Trust (RCT and JNWNB) are most gratefully acknowledged. We wish to record our sincere appreciation for the support of the many dermatologists who have notified us of families with psoriasis and to the patients and their families for their forbearance in participating in these studies.
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*To whom correspondence should be addressed. Tel: +44 116 2 585 736; Fax: +44 116 2 586 057; Email: rtrembat@hgmp.mrc.ac.uk
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