A strong heritability of psoriatic arthritis over four generations--the Reykjavik Psoriatic Arthritis Study.

OBJECTIVE: We have studied the prevalence of PsA in Reykjavik, Iceland, in a population-based cohort, and using the Icelandic genealogy database we have estimated the risk ratio (RR) spanning five generations. METHODS: The national identification numbers of all 220 living Icelanders in Reykjavik known to have PsA were linked with the genealogy database. RRs for developing PsA were estimated in first-degree relatives (FDRs) to fifth-degree relatives of PsA cases. The kinship coefficient (KC) for PsA was also calculated. The control populations were 1000 and 10,000 sets of matched Icelandic subjects for each proband, respectively. RESULTS: FDRs to fourth-degree relatives of patients with PsA had RRs of 39, 12, 3.6 and 2.3, respectively (all P-values < 0.0001), reflecting a strong genetic component, whereas the fifth-degree relatives had an RR of 1.2 (P = 0.236). KCs of 5.0, 3.4, 1.7, 1.3, 1.0, 0.8 and 0.7 were observed for the first seven excluded meioses (all P-values < 0.0001), confirming the familial risk. CONCLUSIONS: Patients with PsA in Reykjavik, Iceland, are significantly more related to each other than to randomly sampled control subjects. This is in agreement with previous reports, but the present study examines the inheritance in more distantly related individuals. These findings indicate that in addition to a strong and complex genetic component in PsA, there is an important environmental contribution.

Distinct clinical differences between HLA-Cw*0602 positive and negative psoriasis patients--an analysis of 1019 HLA-C- and HLA-B-typed patients.

A major susceptibility gene for psoriasis is located in the major histocompatibility complex class I region on chromosome 6 very close to the HLA-Cw6 gene. We collected a cohort of 1,019 patients with chronic plaque psoriasis. The patients were typed for HLA-C and HLA-B. A total of 654 (64.2%) were HLA-Cw*0602 positive but 365 (35.8%) carried other HLA-C alleles. We confirmed that HLA-Cw*0602 positive patients have younger age of onset (17.5 vs 24.3 years, P<10(-10)), higher incidence of guttate and the eruptive type of psoriasis (P<0.0001), more frequent exacerbations with throat infections (P=0.01), higher incidence of the Koebner's phenomenon (P=0.01), and more extensive disease (P=0.03). A striking new finding was a diverging pattern of disease severity in HLA-Cw*0602 positive and negative patients depending on the age of onset of the disease (P=0.0006). HLA-Cw*0602 positive women also had more frequent remissions during pregnancy (P<0.0001). All types of nail changes were, however, more common in the Cw*0602 negative patients (P=0.003) and they more often had multiple types of nail lesions (P<0.0001). The three ancestral haplotypes of Cw*0602 all conferred an increase in odds ratio but showed no difference in any of the clinical features studied. Our findings indicate that the genetic factor on chromosome 6 has a strong influence on the phenotype of the disease, and underline that differences in clinical features of psoriasis may be to a large extent genetically determined.

HLA class II sequence variants influence tuberculosis risk in populations of European ancestry.

Mycobacterium tuberculosis infections cause 9 million new tuberculosis cases and 1.5 million deaths annually. To identify variants conferring risk of tuberculosis, we tested 28.3 million variants identified through whole-genome sequencing of 2,636 Icelanders for association with tuberculosis (8,162 cases and 277,643 controls), pulmonary tuberculosis (PTB) and M. tuberculosis infection. We found association of three variants in the region harboring genes encoding the class II human leukocyte antigens (HLAs): rs557011[T] (minor allele frequency (MAF) = 40.2%), associated with M. tuberculosis infection (odds ratio (OR) = 1.14, P = 3.1 × 10(-13)) and PTB (OR = 1.25, P = 5.8 × 10(-12)), and rs9271378[G] (MAF = 32.5%), associated with PTB (OR = 0.78, P = 2.5 × 10(-12))--both located between HLA-DQA1 and HLA-DRB1--and a missense variant encoding p.Ala210Thr in HLA-DQA1 (MAF = 19.1%, rs9272785), associated with M. tuberculosis infection (P = 9.3 × 10(-9), OR = 1.14). We replicated association of these variants with PTB in samples of European ancestry from Russia and Croatia (P < 5.9 × 10(-4)). These findings show that the HLA class II region contributes to genetic risk of tuberculosis, possibly through reduced presentation of protective M. tuberculosis antigens to T cells.

Genetics of psoriasis in Iceland: evidence for linkage of subphenotypes to distinct Loci.

Psoriasis is a chronic inflammatory skin disease with overlapping subphenotypes. It has a strong complex genetic component, but has been problematic to identifying significant loci. We evaluated 1000 patients with chronic plaque psoriasis and documented several subphenotypes. Here we report results of genome-wide linkage scans for psoriasis genes in 238 Icelandic families with 874 patients. MHC linkage was confirmed with LOD score of 10.9. When the entire cohort was analyzed, two other loci with LOD scores of 2.5 and 1.5 were observed on 16q and 4q, respectively. Stratification into subphenotypes revealed additional loci with LOD scores exceeding or approaching significance. A LOD score of 5.7 appeared on 16q in PsA patients with analysis conditioned on parental inheritance. A LOD score of 3.6 on 4q was detected when disease occurred at or older than 17 y, our median cohort age. This locus was defined by a marker near one reportedly displaying significant linkage in a Chinese psoriasis population and near suggestive linkage in a Caucasian population. A LOD of 3.0 was observed on 10q when disease onset occurred in the scalp. Furthermore, clinical stratification either revealed or increased LOD scores when compared to unstratified analysis and some coincided with previous reports.

HLA-Cw6-positive and HLA-Cw6-negative patients with Psoriasis vulgaris have distinct clinical features.

Psoriasis is associated with HLA-Cw6, and Caucasians who carry this allele have about a 10-fold increased risk of developing psoriasis. We have HLA-C typed 369 patients with familial psoriasis and compared the clinical features of the patients carrying HLA-Cw6 against those carrying other HLA-C types. Some striking clinical differences were observed between the two groups. Patients who are Cw6 positive had a lower age at onset (p=3x10(-7)). Cw6-positive women had an earlier disease onset than Cw6-positive men (p =0.02), but such a difference was not observed for the Cw6-negative patients. The guttate-type onset of psoriasis was mostly confined to this group (p=2x10(-4)) and persistent disseminated guttate-like papules were also predominantly observed in the Cw6-positive patients (p <10(-)4). The Cw6-positive patients also had more extensive plaques on their arms, legs, and trunk (p =0.001), more severe disease (p =0.003), higher incidence of the Koebner's phenomenon (p =0.005), reported more often that their psoriasis got worse during or after throat infections (p =0.02), and more often a favorable response to sunlight (p =0.008) In contrast, dystrophic nail changes were more common in the Cw6-negative patients (p =0.002) and also psoriatic arthritis, although this was not significant (p =0.135). It is concluded that patients with psoriasis have different clinical features depending on whether they are HLA-Cw6 positive or negative.

Androgenetic alopecia: identification of four genetic risk loci and evidence for the contribution of WNT signaling to its etiology.

The pathogenesis of androgenetic alopecia (AGA, male-pattern baldness) is driven by androgens, and genetic predisposition is the major prerequisite. Candidate gene and genome-wide association studies have reported that single-nucleotide polymorphisms (SNPs) at eight different genomic loci are associated with AGA development. However, a significant fraction of the overall heritable risk still awaits identification. Furthermore, the understanding of the pathophysiology of AGA is incomplete, and each newly associated locus may provide novel insights into contributing biological pathways. The aim of this study was to identify unknown AGA risk loci by replicating SNPs at the 12 genomic loci that showed suggestive association (5 × 10(-8)

Identification of low-frequency variants associated with gout and serum uric acid levels.

We tested 16 million SNPs, identified through whole-genome sequencing of 457 Icelanders, for association with gout and serum uric acid levels. Genotypes were imputed into 41,675 chip-genotyped Icelanders and their relatives, for effective sample sizes of 968 individuals with gout and 15,506 individuals for whom serum uric acid measurements were available. We identified a low-frequency missense variant (c.1580C>G) in ALDH16A1 associated with gout (OR = 3.12, P = 1.5 × 10(-16), at-risk allele frequency = 0.019) and serum uric acid levels (effect = 0.36 s.d., P = 4.5 × 10(-21)). We confirmed the association with gout by performing Sanger sequencing on 6,017 Icelanders. The association with gout was stronger in males relative to females. We also found a second variant on chromosome 1 associated with gout (OR = 1.92, P = 0.046, at-risk allele frequency = 0.986) and serum uric acid levels (effect = 0.48 s.d., P = 4.5 × 10(-16)). This variant is close to a common variant previously associated with serum uric acid levels. This work illustrates how whole-genome sequencing data allow the detection of associations between low-frequency variants and complex traits.

Genome-wide association study identifies sequence variants on 6q21 associated with age at menarche.

Earlier menarche correlates with shorter adult height and higher childhood body fat. We conducted a genome-wide association study of age at menarche (AAM) on 15,297 Icelandic women. Combined analysis with replication sets from Iceland, Denmark and the Netherlands (N = 10,040) yielded a significant association between rs314280[T] on 6q21, near the LIN28B gene, and AAM (effect = 1.2 months later per allele; P = 1.8 × 10(-14)). A second SNP within the same linkage disequilibrium (LD) block, rs314277, splits rs314280[T] into two haplotypes with different effects (0.9 months and 1.9 months per allele). These variants have been associated with greater adult height. The association with adult height did not account for the association with AAM or vice versa. Other variants, previously associated with height, did not associate significantly with AAM. Given the link between body fat and AAM, we also assessed 11 variants recently associated with higher body mass index (BMI) and 5 of those associated with earlier AAM.

Genetic determinants of hair, eye and skin pigmentation in Europeans.

Hair, skin and eye colors are highly heritable and visible traits in humans. We carried out a genome-wide association scan for variants associated with hair and eye pigmentation, skin sensitivity to sun and freckling among 2,986 Icelanders. We then tested the most closely associated SNPs from six regions--four not previously implicated in the normal variation of human pigmentation--and replicated their association in a second sample of 2,718 Icelanders and a sample of 1,214 Dutch. The SNPs from all six regions met the criteria for genome-wide significance. A variant in SLC24A4 is associated with eye and hair color, a variant near KITLG is associated with hair color, two coding variants in TYR are associated with eye color and freckles, and a variant on 6p25.3 is associated with freckles. The fifth region provided refinements to a previously reported association in OCA2, and the sixth encompasses previously described variants in MC1R.

Psoriasis: a complex clinical and genetic disorder.

Psoriasis is associated with arthritis in approximately 10% of patients. The skin disease and arthritis have a strong but complex genetic component. Several susceptibility loci have been reported including one major locus that maps very close to the human leukocyte antigen-C gene on chromosome 6p. No causative gene has so far been conclusively identified. A recent genetic analysis that only included patients with psoriatic arthritis revealed a highly significant susceptibility locus on chromosome 16q approximately 20 cM from the NOD2 gene that has been associated with Crohn's disease. This locus was barely detectable when the entire cohort of psoriasis patients was analyzed as a homogeneous entity. A further clinical stratification of psoriasis patients has revealed novel strongly suggestive loci and also increased the logarithm of the odds scores of some previously reported loci. It is concluded that a careful documentation of clinical features and phenotypic stratification may help to analyze complex genetic disorders.

A susceptibility gene for psoriatic arthritis maps to chromosome 16q: evidence for imprinting.

Several genetic loci have been reported for psoriasis, but none has been specifically linked to psoriatic arthritis (PsA), a condition that affects >10% of patients with psoriasis. A genetic component for PsA is suggested by segregation within families and high concordance among identical twins. We performed a linkage scan to map genes contributing to PsA. We identified 178 patients with PsA out of 906 patients who were included in our genetic study of psoriasis. Using a comprehensive genealogy database, we were able to connect 100 of these into 39 families. We genotyped the patients using a framework marker set of 1,000 microsatellite markers, with an average density of 3 cM, and performed multipoint, affected-only, allele-sharing linkage analysis using the Allegro program. On the basis of the initial results, we genotyped more markers for the most prominent loci. A linkage with a LOD score of 2.17 was observed on chromosome 16q. The linkage analysis, conditioned on paternal transmission to affected individuals, gave a LOD score of 4.19, whereas a LOD score of only 1.03 was observed when conditioned for maternal transmission. A suggestive locus on chromosome 16q has previously been implicated in psoriasis. Our data indicate that a gene at this locus may be involved in paternal transmission of PsA.