Psoriatic arthritis (PsA) is an inflammatory joint disease that is distinct from other chronic arthritides and which is frequently accompanied by psoriasis vulgaris (PsV) and seronegativity for rheumatoid factor. We conducted a genome-wide association study in 609 German individuals with PsA (cases) and 990 controls with replication in 6 European cohorts including a total of 5,488 individuals. We replicated PsA associations at HLA-C and IL12B and identified a new association at TRAF3IP2 (rs13190932, P = 8.56 × 10⁻¹⁷). TRAF3IP2 was also associated with PsV in a German cohort including 2,040 individuals (rs13190932, P = 1.95 × 10⁻³). Sequencing of the exons of TRAF3IP2 identified a coding variant (p.Asp10Asn, rs33980500) as the most significantly associated SNP (P = 1.13 × 10⁻²⁰, odds ratio = 1.95). Functional assays showed reduced binding of this TRAF3IP2 variant to TRAF6, suggesting altered modulation of immunoregulatory signals through altered TRAF interactions as a new and shared pathway for PsA and PsV

APOE ε4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer’s Project (IGAP) Consortium in APOE ε4+ (10,352 cases and 9,207 controls) and APOE ε4− (7,184 cases and 26,968 controls) subgroups as well as in the total sample testing for interaction between a SNP and APOE ε4 status. Suggestive associations (P<1x10−4) in stage 1 were evaluated in an independent sample (stage 2) containing 4,203 subjects (APOE ε4+: 1,250 cases and 536 controls; APOE ε4-: 718 cases and 1,699 controls). Among APOE ε4− subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 datasets (best SNP, rs2732703, P=5·8x10−9). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100 kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ε4+ subjects (CR1 and CLU) or APOE ε4− subjects (MS4A6A/MS4A4A/ MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6x10−7) is noteworthy because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P≤1.3x10−8), frontal cortex (P≤1.3x10−9), and temporal cortex (P≤1.2x10−11). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2x10−6) and temporal cortex (P=2.6x10−6). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ε4 compared to persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.

Androgenetic alopecia (AGA) is a highly heritable condition and the most common form of hair loss in humans. Susceptibility loci have been described on the X chromosome and chromosome 20, but these loci explain a minority of its heritable variance. We conducted a large-scale meta-analysis of seven genome-wide association studies for early-onset AGA in 12,806 individuals of European ancestry. While replicating the two AGA loci on the X chromosome and chromosome 20, six novel susceptibility loci reached genome-wide significance (p = 2.62×10−9–1.01×10−12). Unexpectedly, we identified a risk allele at 17q21.31 that was recently associated with Parkinson's disease (PD) at a genome-wide significant level. We then tested the association between early-onset AGA and the risk of PD in a cross-sectional analysis of 568 PD cases and 7,664 controls. Early-onset AGA cases had significantly increased odds of subsequent PD (OR = 1.28, 95% confidence interval: 1.06–1.55, p = 8.9×10−3). Further, the AGA susceptibility alleles at the 17q21.31 locus are on the H1 haplotype, which is under negative selection in Europeans and has been linked to decreased fertility. Combining the risk alleles of six novel and two established susceptibility loci, we created a genotype risk score and tested its association with AGA in an additional sample. Individuals in the highest risk quartile of a genotype score had an approximately six-fold increased risk of early-onset AGA [odds ratio (OR) = 5.78, p = 1.4×10−88]. Our results highlight unexpected associations between early-onset AGA, Parkinson's disease, and decreased fertility, providing important insights into the pathophysiology of these conditions.

herold@imbie.meb.uni-bonn.de; becker@imbie.meb.uni-bonn.de.

Recently, the first genome-wide association study (GWAS) of alopecia areata (AA) was conducted in a North-American sample, and this identified eight susceptibility loci surpassing genome-wide significance. The aim of the present follow-up association analysis was to confirm five of these eight loci (single-nucleotide polymorphisms (SNPs) from the CTLA4, IL-2RA, and HLA regions were not included due to previous own findings) and test 12 other loci from the GWAS, which did not surpass the threshold for genome-wide significance. Twenty-three SNPs from the 17 loci were investigated using a sample of 1,702 Central European AA patients and 1,723 controls. Of the five loci with previously reported genome-wide significance, association was confirmed for all of these: ULBP3/ULBP6, PRDX5, IL-2/IL-21, STX17, and IKZF4/ERBB3 (P-value <0.05). To detect robust evidence for association among the 12 other loci, a meta-analysis of the present association data and the data of the recent GWAS was performed. Genome-wide significant association was found for rs20541 (P(comb)=7.52 × 10(-10); odds ratio (OR)=1.30 (1.23-1.38)) and rs998592 (P(comb)=1.11 × 10(-11); OR=1.28 (1.21-1.36)), thus establishing IL-13 and KIAA0350/CLEC16A as susceptibility loci for AA. Interestingly, IL-13 and KIAA0350/CLEC16A are susceptibility loci for other autoimmune diseases, supporting the hypothesis of shared pathways of autoimmune susceptibility.

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)

The software is available at http://famhap.meb.uni-bonn.de

Male-pattern baldness (MPB) is a common and highly heritable trait characterized by androgen-dependent, progressive hair loss from the scalp. Here, we carry out the largest GWAS meta-analysis of MPB to date, comprising 10,846 early-onset cases and 11,672 controls from eight independent cohorts. We identify 63 MPB-associated loci (P<5 × 10−8, METAL) of which 23 have not been reported previously. The 63 loci explain ∼39% of the phenotypic variance in MPB and highlight several plausible candidate genes (FGF5, IRF4, DKK2) and pathways (melatonin signalling, adipogenesis) that are likely to be implicated in the key-pathophysiological features of MPB and may represent promising targets for the development of novel therapeutic options. The data provide molecular evidence that rather than being an isolated trait, MPB shares a substantial biological basis with numerous other human phenotypes and may deserve evaluation as an early prognostic marker, for example, for prostate cancer, sudden cardiac arrest and neurodegenerative disorders.