Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

Gene flow and the maintenance of species boundaries

Hybrid zones are regions where individuals from genetically differentiated populations meet and mate, resulting in at least some offspring of mixed ancestry. Patterns of gene flow (introgression) in hybrid zones vary across the genome, allowing assessment of the role of individual genes or genome regions in reproductive isolation. Here, we document patterns of introgression between two recently diverged species of field crickets. We sampled at a very fine spatial scale and genotyped crickets for 110 highly differentiated single nucleotide polymorphisms (SNPs) identified through transcriptome scans. Using both genomic and geographic cline analysis, we document remarkably abrupt transitions (<100 m) in allele frequencies for 50 loci, despite high levels of gene flow at other loci. These are among the steepest clines documented for any hybridizing taxa. Furthermore, the cricket hybrid zone provides one of the clearest examples of the semi-permeability of species boundaries. Comparisons between data from the fine-scale transect and data (for the same set of markers) from sampling a much larger area in a different region of the cricket hybrid zone reveal consistent patterns of introgression for individual loci. The consistency in patterns of introgression between these two distant and distinct regions of the hybrid zone suggests that strong selection is acting to maintain abrupt discontinuities within the hybrid zone and that genomic regions with restricted introgression likely include genes that contribute to nonecological prezygotic barriers.

Surgical Technique: Reverse Periacetabular Osteotomy

Acetabular retroversion is the result of an externally rotated hemipelvis rather than a focal overgrowth of the anterior wall and/or hypoplasia of the posterior wall. Acetabular retroversion is a cause of pincer impingement which, if left untreated, can lead to hip pain and osteoarthritis. The causal surgical treatment in hips with acetabular retroversion is acetabular reorientation with a reverse periacetabular osteotomy (PAO). Indication is based on a positive correlation among symptoms (typically groin pain), physical findings on examination (positive anterior impingement test and decreased flexion and internal rotation), and radiographic signs for acetabular retroversion. These include a positive crossover, posterior wall, and ischial spine sign. A reverse PAO is performed with four osteotomies and a controlled fracture. Unlike reorientation of the acetabular fragment in dysplastic hips, correction for acetabular retroversion is achieved by a combined extension and internal rotation of the acetabular fragment. Typically, a small supra-acetabular wedge resection is required to allow sufficient extension of the fragment. The quality of acetabular reorientation is evaluated by intraoperative AP pelvic radiographs. In addition, intraoperative testing of range of motion following acetabular reorientation is mandatory. An arthrotomy and offset correction of the femoral head-neck area is indicated in hips with decreased internal rotation following acetabular reorientation. In a 10-year follow-up study of reverse PAO, a favorable outcome with preservation of all native joints was found. Correct acetabular orientation and, if necessary, a concomitant offset correction were the keys of successful outcome.