Objective: To quantify genetic overlap between migraine and ischemic stroke (IS) with respect to common genetic variation. Methods:We applied 4 different approaches to large-scale meta-analyses of genome-wide data on migraine (23,285 cases and 95,425 controls) and IS (12,389 cases and 62,004 controls). First, we queried known genome-wide significant loci for both disorders, looking for potential overlap of signals. We then analyzed the overall shared genetic load using polygenic scores and estimated the genetic correlation between disease subtypes using data derived from these models. We further interrogated genomic regions of shared risk using analysis of covariance patterns between the 2 phenotypes using cross-phenotype spatial mapping. Results:We found substantial genetic overlap between migraine and IS using all 4 approaches.Migraine without aura (MO) showed much stronger overlap with IS and its subtypes than migraine with aura (MA). The strongest overlap existed between MO and large artery stroke (LAS; p 5 6.4 3 10 228 for the LAS polygenic score in MO) and between MO and cardioembolic stroke (CE; p 5 2.7 3 10 220 for the CE score in MO). Conclusions:Our findings indicate shared genetic susceptibility to migraine and IS, with a particularly strong overlap between MO and both LAS and CE pointing towards shared mechanisms. Our observations on MA are consistent with a limited role of common genetic variants in this subtype. Neurology ® 2015;84:2132-2145 GLOSSARY CE 5 cardioembolic stroke; CPSM 5 cross-phenotype spatial mapping; GWAS 5 genome-wide association studies; IHGC 5 International Headache Genetics Consortium; IS 5 ischemic stroke; LAS 5 large artery stroke; LD 5 linkage disequilibrium; MA 5 migraine with aura; MO 5 migraine without aura; SNP 5 single nucleotide polymorphism; SVD 5 small vessel disease.Migraine is a primary headache disorder characterized by recurrent attacks of severe, often throbbing, headache associated with autonomic dysfunction. Although the majority of patients have migraine without aura (MO), one third have headaches preceded by transient neurologic disturbances (migraine with aura [MA]). 1 Ischemic stroke (IS) is etiologically heterogeneous and a leading cause of premature death and disability. Results of epidemiologic studies show increased risk of IS in migraine patients.3 A large metaanalysis of case-control and observational cohort studies reported an increased risk of IS for patients with MO and MA, 4 whereas more recent meta-analyses reported the association to be restricted to MA. 3,5,6 Pathophysiology linking these neurovascular disorders remains poorly understood; suggested mechanisms include cortical spreading depression, 7 endothelial dysfunction, 8 enhanced platelet activation, 9 and vasoconstriction.

Objective:To apply genetic analysis of genome-wide association data to study the extent and nature of a shared biological basis between migraine and coronary artery disease (CAD).Methods:Four separate methods for cross-phenotype genetic analysis were applied on data from 2 large-scale genome-wide association studies of migraine (19,981 cases, 56,667 controls) and CAD (21,076 cases, 63,014 controls). The first 2 methods quantified the extent of overlapping risk variants and assessed the load of CAD risk loci in migraineurs. Genomic regions of shared risk were then identified by analysis of covariance patterns between the 2 phenotypes and by querying known genome-wide significant loci.Results:We found a significant overlap of genetic risk loci for migraine and CAD. When stratified by migraine subtype, this was limited to migraine without aura, and the overlap was protective in that patients with migraine had a lower load of CAD risk alleles than controls. Genes indicated by 16 shared risk loci point to mechanisms with potential roles in migraine pathogenesis and CAD, including endothelial dysfunction (PHACTR1) and insulin homeostasis (GIP).Conclusions:The results suggest that shared biological processes contribute to risk of migraine and CAD, but surprisingly this commonality is restricted to migraine without aura and the impact is in opposite directions. Understanding the mechanisms underlying these processes and their opposite relationship to migraine and CAD may improve our understanding of both disorders.

BackgroundLeprosy is a disease of the skin and peripheral nervous system caused by the obligate intracellular bacterium Mycobacterium leprae. The clinical presentations of leprosy are spectral, with the severity of disease determined by the balance between the cellular and humoral immune response of the host. The exact mechanisms that facilitate disease susceptibility, onset and progression to certain clinical phenotypes are presently unclear. Various studies have examined lipid metabolism in leprosy, but there has been limited work using whole metabolite profiles to distinguish the clinical forms of leprosy.Methodology and Principal FindingsIn this study we adopted a metabolomics approach using high mass accuracy ultrahigh pressure liquid chromatography mass spectrometry (UPLC-MS) to investigate the circulatory biomarkers in newly diagnosed untreated leprosy patients. Sera from patients having bacterial indices (BI) below 1 or above 4 were selected, subjected to UPLC-MS, and then analyzed for biomarkers which distinguish the polar presentations of leprosy. We found significant increases in the abundance of certain polyunsaturated fatty acids (PUFAs) and phospholipids in the high-BI patients, when contrasted with the levels in the low-BI patients. In particular, the median values of arachidonic acid (2-fold increase), eicosapentaenoic acid (2.6-fold increase) and docosahexaenoic acid (1.6-fold increase) were found to be greater in the high-BI patients.SignificanceEicosapentaenoic acid and docosahexaenoic acid are known to exert anti-inflammatory properties, while arachidonic acid has been reported to have both pro- and anti-inflammatory activities. The observed increase in the levels of several lipids in high-BI patients may provide novel clues regarding the biological pathways involved in the immunomodulation of leprosy. Furthermore, these results may lead to the discovery of biomarkers that can be used to investigate susceptibility to infection, facilitate early diagnosis and monitor the progression of disease.

Tumor-infiltrating lymphocytes (TILs) are critical to anti-cancer immune responses, but their diverse phenotypes and functions remain poorly understood and challenging to study. We therefore developed a single-cell barcoding technology for deep characterization of TILs without the need for cell-sorting or culture. Our emulsion-based method captures full-length, natively paired B-cell and T-cell receptor (BCR and TCR) sequences from lymphocytes among millions of input cells. We validated the method with 3 million B-cells from healthy human blood and 350,000 B-cells from an HIV elite controller, before processing 400,000 cells from an unsorted dissociated ovarian adenocarcinoma and recovering paired BCRs and TCRs from over 11,000 TILs. We then extended the barcoding method to detect DNA-labeled antibodies, allowing ultra-high throughput, simultaneous protein detection and RNA sequencing from single cells.

Leprosy continues to be endemic in parts of China. To track the occurrence of leprosy and determine at risk communities, molecular strain typing based on variable number of tandem repeats (VNTRs) was applied in Qiubei County, Wenshan Prefecture, Yunnan Province of the People's Republic of China, a multiethnic region that is home to four predominant ethnic minorities. A previous study, conducted between 2002 and 2005, provided the first descriptions of Mycobacterium leprae strains in the region. M. leprae strains in Qiubei are highly conserved, so only sufficiently polymorphic loci can distinguish strains. A balance between mutation rate and loci stability is needed, so that secondary transmissions can be identified as genotypic matches. The long incubation period of leprosy necessitated an extension of the study to assess the validity of VNTR typing and observe allelic shifts in the same multiethnic population. From 2006 to early 2010 the extension was performed to yield a cumulative total of 164 enrolled patients and 130 skin samples suitable for VNTR typing. Patient demographic information revealed that the case detection rate among certain minority populations in the county is considerably higher than the national rate. Cluster analysis of allele frequencies showed similar strain types within family groups and neighboring townships. Allele frequencies were not found to significantly differ between genders or clinical presentations. The percentage of cases showing near-matching genotypes varied with geography; showing a considerably higher rate in the northern townships. The northern townships continue to show strain types falling into the groups previously defined. Southern genotypes were distinct from those in the north, but clonal genetic relationships were indiscernible in the south. Social interactions and the physical, residential and occupational environments may be more conducive to transmission of community strains in the north.