Suthesh Sivapalaratnam

The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease

Summary Many common variants have been associated with hematological traits, but identification of causal genes and pathways has proven challenging. We performed a genome-wide association analysis in the UK Biobank and INTERVAL studies, testing 29.5 million genetic variants for association with 36 red cell, white cell, and platelet properties in 173,480 European-ancestry participants. This effort yielded hundreds of low frequency (<5%) and rare (<1%) variants with a strong impact on blood cell phenotypes. Our data highlight general properties of the allelic architecture of complex traits, including the proportion of the heritable component of each blood trait explained by the polygenic signal across different genome regulatory domains. Finally, through Mendelian randomization, we provide evidence of shared genetic pathways linking blood cell indices with complex pathologies, including autoimmune diseases, schizophrenia, and coronary heart disease and evidence suggesting previously reported population associations between blood cell indices and cardiovascular disease may be non-causal.

A high-throughput sequencing test for diagnosing inherited bleeding, thrombotic, and platelet disorders

Inherited bleeding, thrombotic, and platelet disorders (BPDs) are diseases that affect ∼300 individuals per million births. With the exception of hemophilia and von Willebrand disease patients, a molecular analysis for patients with a BPD is often unavailable. Many specialized tests are usually required to reach a putative diagnosis and they are typically performed in a step-wise manner to control costs. This approach causes delays and a conclusive molecular diagnosis is often never reached, which can compromise treatment and impede rapid identification of affected relatives. To address this unmet diagnostic need, we designed a high-throughput sequencing platform targeting 63 genes relevant for BPDs. The platform can call single nucleotide variants, short insertions/deletions, and large copy number variants (though not inversions) which are subjected to automated filtering for diagnostic prioritization, resulting in an average of 5.34 candidate variants per individual. We sequenced 159 and 137 samples, respectively, from cases with and without previously known causal variants. Among the latter group, 61 cases had clinical and laboratory phenotypes indicative of a particular molecular etiology, whereas the remainder had an a priori highly uncertain etiology. All previously detected variants were recapitulated and, when the etiology was suspected but unknown or uncertain, a molecular diagnosis was reached in 56 of 61 and only 8 of 76 cases, respectively. The latter category highlights the need for further research into novel causes of BPDs. The ThromboGenomics platform thus provides an affordable DNA-based test to diagnose patients suspected of having a known inherited BPD.

Adult height, coronary heart disease and stroke: a multi-locus Mendelian randomization meta-analysis

Abstract Background: We investigated causal effect of completed growth, measured by adult height, on coronary heart disease (CHD), stroke and cardiovascular traits, using instrumental variable (IV) Mendelian randomization meta-analysis. Methods: We developed an allele score based on 69 single nucleotide polymorphisms (SNPs) associated with adult height, identified by the IBCCardioChip, and used it for IV analysis against cardiovascular risk factors and events in 21 studies and 60u2009028 participants. IV analysis on CHD was supplemented by summary data from 180 height-SNPs from the GIANT consortium and their corresponding CHD estimates derived from CARDIoGRAMplusC4D. Results: IV estimates from IBCCardioChip and GIANT-CARDIoGRAMplusC4D showed that a 6.5-cm increase in height reduced the odds of CHD by 10% [odds ratios 0.90; 95% confidence intervals (CIs): 0.78 to 1.03 and 0.85 to 0.95, respectively],which agrees with the estimate from the Emerging Risk Factors Collaboration (hazard ratio 0.93; 95% CI: 0.91 to 0.94). IV analysis revealed no association with stroke (odds ratio 0.97; 95% CI: 0.79 to 1.19). IV analysis showed that a 6.5-cm increase in height resulted in lower levels of body mass index (Pu2009<u20090.001), triglycerides (Pu2009<u20090.001), non high-density (non-HDL) cholesterol (Pu2009<u20090.001), C-reactive protein (Pu2009=u20090.042), and systolic blood pressure (Pu2009=u20090.064) and higher levels of forced expiratory volume in 1u2009s and forced vital capacity (Pu2009<u20090.001 for both). Conclusions: Taller individuals have a lower risk of CHD with potential explanations being that taller people have a better lung function and lower levels of body mass index, cholesterol and blood pressure.

Rare variants in GP1BB are responsible for autosomal dominant macrothrombocytopenia

The von Willebrand receptor complex, which is composed of the glycoproteins Ibα, Ibβ, GPV, and GPIX, plays an essential role in the earliest steps in hemostasis. During the last 4 decades, it has become apparent that loss of function of any 1 of 3 of the genes encoding these glycoproteins (namely, GP1BA, GP1BB, and GP9) leads to autosomal recessive macrothrombocytopenia complicated by bleeding. A small number of variants in GP1BA have been reported to cause a milder and dominant form of macrothrombocytopenia, but only 2 tentative reports exist of such a variant in GP1BB By analyzing data from a collection of more than 1000 genome-sequenced patients with a rare bleeding and/or platelet disorder, we have identified a significant association between rare monoallelic variants in GP1BB and macrothrombocytopenia. To strengthen our findings, we sought further cases in 2 additional collections in the United Kingdom and Japan. Across 18 families exhibiting phenotypes consistent with autosomal dominant inheritance of macrothrombocytopenia, we report on 27 affected cases carrying 1 of 9 rare variants in GP1BB.

Diagnosis of inherited bleeding disorders in the genomic era

Inherited bleeding disorders affect between 1 in 1000 individuals for the most common disorder, von Willebrand Disease, to only 8 reported cases worldwide of alpha‐2‐antiplasmin deficiency. Those with an identifiable abnormality can be divided into disorders of coagulation factors (87%), platelet count and function (8%) and the fibrinolytic system (3%). Of the patients registered in the UK with a bleeding disorder, the remaining 2% are unclassifiable. In addition to bleeding symptoms, patients with an inherited bleeding disorder can manifest other abnormalities, making an accurate and complete diagnosis that reflects the underlying molecular pathology important. Although some inherited bleeding disorders can still be easily diagnosed through a combination of careful clinical assessment and laboratory assays of varying degrees of complexity, there are many where conventional approaches are inadequate. Improvements in phenotyping assays have enhanced our diagnostic armoury but genotyping now offers the most accurate and complete diagnosis for some of these conditions. The advent of next generation sequencing technology has meant that many genes can now be analysed routinely in clinical practice. Here, we discuss the different diagnostic tools currently available for inherited bleeding disorders and suggest that genotyping should be incorporated at an early stage in the diagnostic pathway.

Disseminated intravascular coagulation: an update on pathogenesis and diagnosis

ABSTRACT Introduction: Activation of the hemostatic system can occur in many clinical conditions. However, a systemic and strong activation of coagulation complicating clinical settings such as sepsis, trauma or malignant disease may result in the occurrence disseminated intravascular coagulation (DIC). Areas covered: This article reviews the clinical manifestation and relevance of DIC, the various conditions that may precipitate DIC and the pathogenetic pathways underlying the derangement of the hemostatic system, based on clinical and experimental studies. In addition, the (differential) diagnostic approach to DIC is discussed. Expert commentary: In recent years a lot of precise insights in the pathophysiology of DIC have been uncovered, leading to a better understanding of pathways leading to the hemostatic derangement and providing points of impact for better adjunctive treatment strategies. In addition, simple diagnostic algorithms have been developed and validated to establish a diagnosis of DIC in clinical practice.