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Chronic venous disease (CVD) is a multifactorial condition representing one of the most common disorders among populations of Western countries. The heritability of about 17% suggests genetic risk factors in CVD etiology. However, so far the genetic causes are unknown. We undertook the hitherto first genome-wide association study (GWAS) for CVD, analyzing more than 1.93 M SNPs in 4,942 German individuals, followed by replication in two independent German data sets. The combined analysis of discovery and replication stages (2,269 cases and 7,765 controls) yielded robust associations within the two genes EFEMP1 and KCNH8 (rs17278665, rs727139 with P −8), and suggestive association within gene SKAP2 (rs2030136 with P −7). Association signals of rs17278665 and rs727139 reside in regions of low linkage disequilibrium containing no other genes. Data from the ENCODE and Roadmap Epigenomics projects show that tissue specific marks overlap with the variants. SNPs rs17278665 and rs2030136 are known eQTLs. Our study demonstrates that GWAS are a valuable tool to study the genetic component of CVD. With our approach, we identified two novel genome-wide significant susceptibility loci for this common disease. Particularly, the extracellular matrix glycoprotein EFEMP1 is promising for future functional studies due to its antagonistic role in vessel development and angiogenesis.

Varicose veins without skin changes have a prevalence of approximately 20% in Northern and Western Europe whereas advanced chronic venous insufficiency affects about 3% of the population. Genetic risk factors are thought to play an important role in the aetiology of both these chronic venous diseases (CVD). We evaluated the relative genetic and environmental impact upon CVD risk by estimating the heritability of the disease in 4,033 nuclear families, comprising 16,434 individuals from all over Germany. Upon clinical examination, patients were classified according to the CEAP guidelines as either C2 (simple varicose veins), C3 (oedema), C4 (skin changes without ulceration), C5 (healed ulceration), or C6 (active ulcers). The narrow-sense heritability (h2) of CVD equals 17.3% (standard error 2.5%, likelihood ratio test P = 1.4 x 10(-13)). The proportion of disease risk attributable to age (at ascertainment) and sex, the two main risk factors for CVD, was estimated as 10.7% (Kullback-Leibler deviance R2). The heritability of CVD is high, thereby suggesting a notable genetic component in the aetiology of the disease. Systematic population-based searches for CVD susceptibility genes are therefore warranted.

Polymorphisms in the interleukin-1 (IL1) gene have been suggested to influence transcription of IL1A (interleukin-1α) and IL1B (interleukin-1β) and thereby the pathophysiology of periodontitis. This case-control association study on 415 northern European Caucasian patients with aggressive periodontitis (AgP) and 874 healthy controls was conducted to examine 10 single-nucleotide polymorphisms (SNPs) in the genes of the IL1 cluster for association with IL1A, IL1B, CKAP2L (cytoskeleton-associated protein 2-like), and IL1RN (IL-1 receptor antagonist). The results do not support an association between variants in the IL1 gene cluster and AgP. This case-control study had at least 95% power to detect genuine associations with variants carrying relative risks of at least 1.5 for heterozygous carriers and 2.25 for homozygous carriers. Previous reports of an association between IL1 promoter SNPs and periodontitis might reflect subpopulation effects and have to be interpreted with care.

Experiments with one-dimensional arrays of Josephson junctions in the regime of dominating charging energy show that the Coulomb blockade is lifted at the threshold voltage, which is proportional to the array's length and depends strongly on the Josephson energy. We explain this behavior as de-pinning of the Cooper-pair-charge-density by the applied voltage. We assume strong charge disorder and argue that physics around the de-pinning point is governed by a disordered sine-Gordon-like model. This allows us to employ the well-known theory of charge density wave de-pinning. Our model is in good agreement with the experimental data., Main: 4 pages, 2 figures, Appendix: 3 pages, 4 figures

Attention deficit hyperactivity disorder (ADHD) is a common and persistent condition characterized by developmentally atypical and impairing inattention, hyperactivity, and impulsiveness. We identified de novo and rare copy number variations (CNVs) in 248 unrelated ADHD patients using million-feature genotyping arrays. We found de novo CNVs in 3 of 173 (1.7%) ADHD patients for whom we had DNA from both parents. These CNVs affected brain-expressed genes: DCLK2, SORCS1, SORCS3, and MACROD2. We also detected rare inherited CNVs in 19 of 248 (7.7%) ADHD probands, which were absent in 2357 controls and which either overlapped previously implicated ADHD loci (for example, DRD5 and 15q13 microduplication) or identified new candidate susceptibility genes (ASTN2, CPLX2, ZBBX, and PTPRN2). Among these de novo and rare inherited CNVs, there were also examples of genes (ASTN2, GABRG1, and CNTN5) previously implicated by rare CNVs in other neurodevelopmental conditions including autism spectrum disorder (ASD). To further explore the overlap of risks in ADHD and ASD, we used the same microarrays to test for rare CNVs in an independent, newly collected cohort of 349 unrelated individuals with a primary diagnosis of ASD. Deletions of the neuronal ASTN2 and the ASTN2-intronic TRIM32 genes yielded the strongest association with ADHD and ASD, but numerous other shared candidate genes (such as CHCHD3, MACROD2, and the 16p11.2 region) were also revealed. Our results provide support for a role for rare CNVs in ADHD risk and reinforce evidence for the existence of common underlying susceptibility genes for ADHD, ASD, and other neuropsychiatric disorders.

Background: NOD proteins are part of innate immunity mechanisms. They play a role in epithelial barrier functions and inflammatory responses to bacteria. Single nucleotide polymorphisms (SNPs) in the NOD1 gene have proven to be associated with inflammatory bowel disease (IBD) and asthma. Objective: To investigate SNPs in the NOD1 gene in relation to aggressive periodontitis (AgP), a multifactorial, inflammatory disease of the supporting tissues of the teeth. Materials and Methods: Five SNPs in the NOD1 gene (4 intronic and 1 exonic) were tested for association in a total of 415 AgP patients and 874 controls both of Northern European ancestry. Results: The frequencies of the rare SNP alleles ranged between 21% and 26% among cases, and 20—27% among controls, and were not statistically different between cases and controls. Two SNPs were in strong linkage disequilibrium (r2 = 0.97 in cases and 0.94 in controls). The overall haplotype distributions did not differ between cases and controls. We observed 8 haplotypes with a frequency of !1% among cases and/or controls, but none of these haplotype frequencies differed significantly among cases and controls. Logistic regression analyses with adjustment for gender and smoking status did not reveal significant associations with AgP for any of the 5 SNPs. This study had a power of !95% to detect associations with variants carrying relative risks of !1.5 for heterozygote carriers and !2.25 for homozygote carriers. Conclusions: Although SNPs in the NOD1 gene have been strongly associated with cases of IBD, the current study failed to show an association of NOD1 SNPs with AgP.

Structural variation (copy number variation [CNV] including deletion and duplication, translocation, inversion) of chromosomes has been identified in some individuals with autism spectrum disorder (ASD), but the full etiologic role is unknown. We performed genome-wide assessment for structural abnormalities in 427 unrelated ASD cases via single-nucleotide polymorphism microarrays and karyotyping. With microarrays, we discovered 277 unbalanced CNVs in 44% of ASD families not present in 500 controls (and re-examined in another 1152 controls). Karyotyping detected additional balanced changes. Although most variants were inherited, we found a total of 27 cases with de novo alterations, and in three (11%) of these individuals, two or more new variants were observed. De novo CNVs were found in approximately 7% and approximately 2% of idiopathic families having one child, or two or more ASD siblings, respectively. We also detected 13 loci with recurrent/overlapping CNV in unrelated cases, and at these sites, deletions and duplications affecting the same gene(s) in different individuals and sometimes in asymptomatic carriers were also found. Notwithstanding complexities, our results further implicate the SHANK3-NLGN4-NRXN1 postsynaptic density genes and also identify novel loci at DPP6-DPP10-PCDH9 (synapse complex), ANKRD11, DPYD, PTCHD1, 15q24, among others, for a role in ASD susceptibility. Our most compelling result discovered CNV at 16p11.2 (p = 0.002) (with characteristics of a genomic disorder) at approximately 1% frequency. Some of the ASD regions were also common to mental retardation loci. Structural variants were found in sufficiently high frequency influencing ASD to suggest that cytogenetic and microarray analyses be considered in routine clinical workup.

Chloroplast RNA editing proceeds by C-to-U transitions at highly specific sites. Here, we provide a phylogenetic analysis of RNA editing in a small plastid gene, petL, encoding subunit VI of the cytochrome b6f complex. Analyzing representatives from most major groups of seed plants, we find an unexpectedly high frequency and dynamics of RNA editing. High-frequency editing has previously been observed in plastid ndh genes, which are remarkable in that their mutational inactivation does not produce an obvious mutant phenotype. In order to test the idea that reduced functional constraints allow for more flexible evolution of RNA editing sites, we have created petL knockout plants by tobacco chloroplast transformation. We find that, in the higher plant tobacco, targeted inactivation of petL does not impair plant growth under a variety of conditions markedly contrasting the important role of petL in photosynthesis in the green alga Chlamydomonas reinhardtii. Together with a low number of editing sites in plastid genes that are essential to gene expression and photosynthetic activity, these data suggest that RNA editing sites may evolve more readily in those genes whose transitory loss of function can be tolerated. Accumulated evidence for this ‘relative neutrality hypothesis for the evolution of plastid editing sites’ is discussed.