Accelerating Haplotype-Based Genome-Wide Association Study Using Perfect Phylogeny and Phase-Known Reference Data

The genome-wide association study (GWAS) has become a routine approach for mapping disease risk loci with the advent of large-scale genotyping technologies. Multi-allelic haplotype markers can provide superior power compared with single-SNP markers in mapping disease loci. However, the application of haplotype-based analysis to GWAS is usually bottlenecked by prohibitive time cost for haplotype inference, also known as phasing. In this study, we developed an efficient approach to haplotype-based analysis in GWAS. By using a reference panel, our method accelerated the phasing process and reduced the potential bias generated by unrealistic assumptions in phasing process. The haplotype-based approach delivers great power and no type I error inflation for association studies. With only a medium-size reference panel, phasing error in our method is comparable to the genotyping error afforded by commercial genotyping solutions

Differential genetic associations for systemic lupus erythematosus based on anti-dsDNA autoantibody production

Systemic lupus erythematosus (SLE) is a clinically heterogeneous, systemic autoimmune disease characterized by autoantibody formation. Previously published genome-wide association studies (GWAS) have investigated SLE as a single phenotype. Therefore, we conducted a GWAS to identify genetic factors associated with anti-dsDNA autoantibody production, a SLE-related autoantibody with diagnostic and clinical importance. Using two independent datasets, over 400,000 single nucleotide polymorphisms (SNPs) were studied in a total of 1,717 SLE cases and 4,813 healthy controls. Anti-dsDNA autoantibody positive (anti-dsDNA +, n = 811) and anti-dsDNA autoantibody negative (anti-dsDNA -, n = 906) SLE cases were compared to healthy controls and to each other to identify SNPs associated specifically with these SLE subtypes. SNPs in the previously identified SLE susceptibility loci STAT4, IRF5, ITGAM, and the major histocompatibility complex were strongly associated with anti-dsDNA + SLE. Far fewer and weaker associations were observed for anti-dsDNA - SLE. For example, rs7574865 in STAT4 had an OR for anti-dsDNA + SLE of 1.77 (95% CI 1.57-1.99, p = 2.0E-20) compared to an OR for anti-dsDNA - SLE of 1.26 (95% CI 1.12-1.41, p = 2.4E-04), with pheterogeneity<0.0005. SNPs in the SLE susceptibility loci BANK1, KIAA1542, and UBE2L3 showed evidence of association with anti-dsDNA + SLE and were not associated with anti-dsDNA - SLE. In conclusion, we identified differential genetic associations with SLE based on anti-dsDNA autoantibody production. Many previously identified SLE susceptibility loci may confer disease risk through their role in autoantibody production and be more accurately described as autoantibody propensity loci. Lack of strong SNP associations may suggest that other types of genetic variation or non-genetic factors such as environmental exposures have a greater impact on susceptibility to anti-dsDNA - SLE

Interactions between genes involved in the antioxidant defence system and breast cancer risk

The aim of the study is to examine the association between multilocus genotypes across 10 genes encoding proteins in the antioxidant defence system and breast cancer. The 10 genes are SOD1, SOD2, GPX1, GPX4, GSR, CAT, TXN, TXN2, TXNRD1 and TXNRD2. In all, 2271 cases and 2280 controls were used to examine gene–gene interactions between 52 single nucleotide polymorphisms (SNPs) that are hypothesised to tag all common variants in the 10 genes. The statistical analysis is based on three methods: unconditional logistic regression, multifactor dimensionality reduction and hierarchical cluster analysis. We examined all two- and three-way combinations with unconditional logistic regression and multifactor dimensionality reduction, and used a global approach with all SNPs in the hierarchical cluster analysis. Single-locus studies of an association of genetic variants in the antioxidant defence genes and breast cancer have been contradictory and inconclusive. It is the first time, to our knowledge, the association between multilocus genotypes across genes coding for antioxidant defence enzymes and breast cancer is investigated. We found no evidence of an association with breast cancer with our multilocus approach. The search for two-way interactions gave experiment-wise significance levels of P=0.24 (TXN [t2715c] and TXNRD2 [g23524a]) and P=0.58 (GSR [c39396t] and TXNRD2 [a442g]), for the unconditional logistic regression and multifactor dimensionality reduction, respectively. The experiment-wise significance levels for the three-way interactions were P=0.94 (GPX4 [t2572c], TXN [t2715c] and TXNRD2 [g23524a]) and P=0.29 (GSR [c39396t], TXN [t2715c] and TXNRD2 [a442g]) for the unconditional logistic regression and multifactor dimensionality reduction, respectively. In the hierarchical cluster analysis neither the average across four rounds with replacement of missing values at random (P=0.12) nor a fifth round with more balanced proportion of missing values between cases and controls (P=0.17) was significant

A 32 kb Critical Region Excluding Y402H in CFH Mediates Risk for Age-Related Macular Degeneration

Complement factor H shows very strong association with Age-related Macular Degeneration (AMD), and recent data suggest that multiple causal variants are associated with disease. To refine the location of the disease associated variants, we characterized in detail the structural variation at CFH and its paralogs, including two copy number polymorphisms (CNP), CNP147 and CNP148, and several rare deletions and duplications. Examination of 34 AMD-enriched extended families (N = 293) and AMD cases (White N = 4210 Indian = 134; Malay = 140) and controls (White N = 3229; Indian = 117; Malay = 2390) demonstrated that deletion CNP148 was protective against AMD, independent of SNPs at CFH. Regression analysis of seven common haplotypes showed three haplotypes, H1, H6 and H7, as conferring risk for AMD development. Being the most common haplotype H1 confers the greatest risk by increasing the odds of AMD by 2.75-fold (95% CI = [2.51, 3.01]; p = 8.31×10−109); Caucasian (H6) and Indian-specific (H7) recombinant haplotypes increase the odds of AMD by 1.85-fold (p = 3.52×10−9) and by 15.57-fold (P = 0.007), respectively. We identified a 32-kb region downstream of Y402H (rs1061170), shared by all three risk haplotypes, suggesting that this region may be critical for AMD development. Further analysis showed that two SNPs within the 32 kb block, rs1329428 and rs203687, optimally explain disease association. rs1329428 resides in 20 kb unique sequence block, but rs203687 resides in a 12 kb block that is 89% similar to a noncoding region contained in ΔCNP148. We conclude that causal variation in this region potentially encompasses both regulatory effects at single markers and copy number

Brace technology thematic series - The Sforzesco and Sibilla braces, and the SPoRT (Symmetric, Patient oriented, Rigid, Three-dimensional, active) concept

<p>Abstract</p> <p>Background</p> <p>Bracing is an effective strategy for scoliosis treatment, but there is no consensus on the best type of brace, nor on the way in which it should act on the spine to achieve good correction. The aim of this paper is to present the family of SPoRT (Symmetric, Patient-oriented, Rigid, Three-dimensional, active) braces: Sforzesco (the first introduced), Sibilla and Lapadula.</p> <p>Methods</p> <p>The Sforzesco brace was developed following specific principles of correction. Due to its overall symmetry, the brace provides space over pathological depressions and pushes over elevations. Correction is reached through construction of the envelope, pushes, escapes, stops, and drivers. The real novelty is the drivers, introduced for the first time with the Sforzesco brace; they allow to achieve the main action of the brace: a three-dimensional elongation pushing the spine in a down-up direction.</p> <p>Brace prescription is made plane by plane: frontal (on the "slopes", another novelty of this concept, i.e. the laterally flexed sections of the spine), horizontal, and sagittal. The brace is built modelling the trunk shape obtained either by a plaster cast mould or by CAD-CAM construction. Brace checking is essential, since SPoRT braces are adjustable and customisable according to each individual curve pattern.</p> <p>Treatment time and duration is individually tailored (18-23 hours per day until Risser 3, then gradual reduction). SEAS (Scientific Exercises Approach to Scoliosis) exercises are a key factor to achieve success.</p> <p>Results</p> <p>The Sforzesco brace has shown to be more effective than the Lyon brace (matched case/control), equally effective as the Risser plaster cast (prospective cohort with retrospective controls), more effective than the Risser cast + Lyon brace in treating curves over 45 degrees Cobb (prospective cohort), and is able to improve aesthetic appearance (prospective cohort).</p> <p>Conclusions</p> <p>The SPoRT concept of bracing (three-dimensional elongation pushing in a down-up direction) is different from the other corrective systems: 3-point, traction, postural, and movement-based. The Sforzesco brace, being comparable to casting, may be the best brace for the worst cases.</p

Genetic Epidemiology of Tuberculosis Susceptibility: Impact of Study Design

Several candidate gene studies have provided evidence for a role of host genetics in susceptibility to tuberculosis (TB). However, the results of these studies have been very inconsistent, even within a study population. Here, we review the design of these studies from a genetic epidemiological perspective, illustrating important differences in phenotype definition in both cases and controls, consideration of latent M. tuberculosis infection versus active TB disease, population genetic factors such as population substructure and linkage disequilibrium, polymorphism selection, and potential global differences in M. tuberculosis strain. These considerable differences between studies should be accounted for when examining the current literature. Recommendations are made for future studies to further clarify the host genetics of TB

A Large-Scale Rheumatoid Arthritis Genetic Study Identifies Association at Chromosome 9q33.2

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease affecting both joints and extra-articular tissues. Although some genetic risk factors for RA are well-established, most notably HLA-DRB1 and PTPN22, these markers do not fully account for the observed heritability. To identify additional susceptibility loci, we carried out a multi-tiered, case-control association study, genotyping 25,966 putative functional SNPs in 475 white North American RA patients and 475 matched controls. Significant markers were genotyped in two additional, independent, white case-control sample sets (661 cases/1322 controls from North America and 596 cases/705 controls from The Netherlands) identifying a SNP, rs1953126, on chromosome 9q33.2 that was significantly associated with RA (ORcommon = 1.28, trend Pcomb = 1.45E-06). Through a comprehensive fine-scale-mapping SNP-selection procedure, 137 additional SNPs in a 668 kb region from MEGF9 to STOM on 9q33.2 were chosen for follow-up genotyping in a staged-approach. Significant single marker results (Pcomb<0.01) spanned a large 525 kb region from FBXW2 to GSN. However, a variety of analyses identified SNPs in a 70 kb region extending from the third intron of PHF19 across TRAF1 into the TRAF1-C5 intergenic region, but excluding the C5 coding region, as the most interesting (trend Pcomb: 1.45E-06 → 5.41E-09). The observed association patterns for these SNPs had heightened statistical significance and a higher degree of consistency across sample sets. In addition, the allele frequencies for these SNPs displayed reduced variability between control groups when compared to other SNPs. Lastly, in combination with the other two known genetic risk factors, HLA-DRB1 and PTPN22, the variants reported here generate more than a 45-fold RA-risk differential

An Integration of Genome-Wide Association Study and Gene Expression Profiling to Prioritize the Discovery of Novel Susceptibility Loci for Osteoporosis-Related Traits

Osteoporosis is a complex disorder and commonly leads to fractures in elderly persons. Genome-wide association studies (GWAS) have become an unbiased approach to identify variations in the genome that potentially affect health. However, the genetic variants identified so far only explain a small proportion of the heritability for complex traits. Due to the modest genetic effect size and inadequate power, true association signals may not be revealed based on a stringent genome-wide significance threshold. Here, we take advantage of SNP and transcript arrays and integrate GWAS and expression signature profiling relevant to the skeletal system in cellular and animal models to prioritize the discovery of novel candidate genes for osteoporosis-related traits, including bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN), as well as geometric indices of the hip (femoral neck-shaft angle, NSA; femoral neck length, NL; and narrow-neck width, NW). A two-stage meta-analysis of GWAS from 7,633 Caucasian women and 3,657 men, revealed three novel loci associated with osteoporosis-related traits, including chromosome 1p13.2 (RAP1A, p = 3.6×10−8), 2q11.2 (TBC1D8), and 18q11.2 (OSBPL1A), and confirmed a previously reported region near TNFRSF11B/OPG gene. We also prioritized 16 suggestive genome-wide significant candidate genes based on their potential involvement in skeletal metabolism. Among them, 3 candidate genes were associated with BMD in women. Notably, 2 out of these 3 genes (GPR177, p = 2.6×10−13; SOX6, p = 6.4×10−10) associated with BMD in women have been successfully replicated in a large-scale meta-analysis of BMD, but none of the non-prioritized candidates (associated with BMD) did. Our results support the concept of our prioritization strategy. In the absence of direct biological support for identified genes, we highlighted the efficiency of subsequent functional characterization using publicly available expression profiling relevant to the skeletal system in cellular or whole animal models to prioritize candidate genes for further functional validation