Genome sequencing unveils a regulatory landscape of platelet reactivity

Platelet aggregation at the site of atherosclerotic vascular injury is the underlying pathophysiology of myocardial infarction and stroke. To build upon prior GWAS, here we report on 16 loci identified through a whole genome sequencing (WGS) approach in 3,855 NHLBI Trans-Omics for Precision Medicine (TOPMed) participants deeply phenotyped for platelet aggregation. We identify the RGS18 locus, which encodes a myeloerythroid lineage-specific regulator of G-protein signaling that co-localizes with expression quantitative trait loci (eQTL) signatures for RGS18 expression in platelets. Gene-based approaches implicate the SVEP1 gene, a known contributor of coronary artery disease risk. Sentinel variants at RGS18 and PEAR1 are associated with thrombosis risk and increased gastrointestinal bleeding risk, respectively. Our WGS findings add to previously identified GWAS loci, provide insights regarding the mechanism(s) by which genetics may influence cardiovascular disease risk, and underscore the importance of rare variant and regulatory approaches to identifying loci contributing to complex phenotypes

The genetic determinants of recurrent somatic mutations in 43,693 blood genomes

Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences

Metabolic syndrome predictors of brain gray matter volume in an age-stratified community sample of 776 Mexican- American adults: Results from the genetics of brain structure image archive

Introduction: This project aimed to investigate the association between biometric components of metabolic syndrome (MetS) with gray matter volume (GMV) obtained with magnetic resonance imaging (MRI) from a large cohort of community-based adults (n = 776) subdivided by age and sex and employing brain regions of interest defined previously as the “Neural Signature of MetS” (NS-MetS). Methods: Lipid profiles, biometrics, and regional brain GMV were obtained from the Genetics of Brain Structure (GOBS) image archive. Participants underwent T1-weighted MR imaging. MetS components (waist circumference, fasting plasma glucose, triglycerides, HDL cholesterol, and blood pressure) were defined using the National Cholesterol Education Program Adult Treatment Panel III. Subjects were grouped by age: early adult (18–25 years), young adult (26–45 years), and middle-aged adult (46–65 years). Linear regression modeling was used to investigate associations between MetS components and GMV in five brain regions comprising the NS-MetS: cerebellum, brainstem, orbitofrontal cortex, right insular/limbic cluster and caudate. Results: In both men and women of each age group, waist circumference was the single component most strongly correlated with decreased GMV across all NS-MetS regions. The brain region most strongly correlated to all MetS components was the posterior cerebellum. Conclusion: The posterior cerebellum emerged as the region most significantly associated with MetS individual components, as the only region to show decreased GMV in young adults, and the region with the greatest variance between men and women. We propose that future studies investigating neurological effects of MetS and its comorbidities—namely diabetes and obesity—should consider the NS-MetS and the differential effects of age and sex

Serum phosphatidylinositol as a biomarker for bipolar disorder liability

Objectives Individuals with bipolar disorder (BPD) exhibit alterations in their phospholipid levels. It is unclear whether these alterations are a secondary consequence of illness state, or if phospholipids and illness risk overlap genetically. If the latter were true, then phospholipids might provide key insights into the pathophysiology of the illness. Therefore, we rank-ordered phospholipid classes by their genetic overlap with BPD risk in order to establish which class might be most informative in terms of increasing our understanding of illness pathophysiology. Methods Analyses were conducted in a sample of 558 individuals, unselected for BPD, from 38 extended pedigrees (average family size=14.79, range=2–82). We calculated a coefficient of relatedness for all family members of nine individuals with BPD in the sample (N=185); this coefficient was set to be zero in unrelated individuals (N=373). Then, under an endophenotype ranking value (ERV) approach, this scalar index was tested against 13 serum-based phospholipid concentrations in order to rank-order lipid classes by their respective overlap with BPD risk. Results The phosphatidylinositol class was significantly heritable (h2=0.26, P=6.71 × 10−05). It was the top-ranked class, and was significantly associated with BPD risk after correction for multiple testing (β=−1.18, P=2.10 × 10−03, ERV=0.49). Conclusions We identified a peripheral biomarker, serum-based phosphatidylinositol, which exhibits a significant association with BPD risk. Therefore, given that phosphatidylinositol and BPD risk share partially common etiology, it seems that this lipid class warrants further investigation, not only in terms of treatment, but also as a promising diagnostic and risk marker

The Lipidome in Major Depressive Disorder: Shared Genetic Influence for Ether-Phosphatidylcholines, a Plasma-Based Phenotype Related to Inflammation, and Disease Risk

Background The lipidome is rapidly garnering interest in the field of psychiatry. Recent studies have implicated lipidomic changes across numerous psychiatric disorders. In particular there is growing evidence that the concentrations of several classes of lipids are altered in those diagnosed with MDD. However, for lipidomic abnormalities to be considered potential treatment targets for MDD (rather than secondary manifestations of the disease), a shared etiology between lipid concentrations and MDD should be demonstrated. Methods In a sample of 567 individuals from 37 extended pedigrees (average size 13.57 people, range = 3–80), we used mass-spectrometry lipidomic measures to evaluate the genetic overlap between twenty-three biologically distinct lipid classes and a dimensional scale of MDD. Results We found that the lipid class with the largest endophenotype ranking value (ERV, a standardized parametric measure of pleiotropy) were ether-phosphodatidylcholines (alkylphosphatidylcholine, PC(O) and alkenylphosphatidylcholine, PC(P) subclasses). Furthermore, we examined the cluster structure of the twenty-five species within the top-ranked lipid class, and the relationship of those clusters with MDD. This analysis revealed that species containing arachidonic acid generally exhibited the greatest degree of genetic overlap with MDD. Conclusions This study is the first to demonstrate a shared genetic etiology between MDD and ether-phosphatidylcholine species containing arachidonic acid, an omega-6 fatty acid that is a precursor to inflammatory mediators, such as prostaglandins. The study highlights the potential utility of the well-characterized linoleic/arachidonic acid inflammation pathway as a diagnostic marker and/or treatment target for MDD

Cocktail-party listening and cognitive abilities show strong pleiotropy

Introduction: The cocktail-party problem refers to the difficulty listeners face when trying to attend to relevant sounds that are mixed with irrelevant ones. Previous studies have shown that solving these problems relies on perceptual as well as cognitive processes. Previously, we showed that speech-reception thresholds (SRTs) on a cocktail-party listening task were influenced by genetic factors. Here, we estimated the degree to which these genetic factors overlapped with those influencing cognitive abilities. Methods: We measured SRTs and hearing thresholds (HTs) in 493 listeners, who ranged in age from 18 to 91 years old. The same individuals completed a cognitive test battery comprising 18 measures of various cognitive domains. Individuals belonged to large extended pedigrees, which allowed us to use variance component models to estimate the narrow-sense heritability of each trait, followed by phenotypic and genetic correlations between pairs of traits. Results: All traits were heritable. The phenotypic and genetic correlations between SRTs and HTs were modest, and only the phenotypic correlation was significant. By contrast, all genetic SRT-cognition correlations were strong and significantly different from 0. For some of these genetic correlations, the hypothesis of complete pleiotropy could not be rejected. Discussion: Overall, the results suggest that there was substantial genetic overlap between SRTs and a wide range of cognitive abilities, including abilities without a major auditory or verbal component. The findings highlight the important, yet sometimes overlooked, contribution of higher-order processes to solving the cocktail-party problem, raising an important caveat for future studies aiming to identify specific genetic factors that influence cocktail-party listening

Family-based analyses reveal novel genetic overlap between cytokine interleukin-8 and risk for suicide attempt

Background: Suicide is major public health concern. It is imperative to find robust biomarkers so that at-risk individuals can be identified in a timely and reliable manner. Previous work suggests mechanistic links between increased cytokines and risk for suicide, but questions remain regarding the etiology of this association, as well as the roles of sex and BMI. Methods: Analyses were conducted using a randomly-ascertained extended-pedigree sample of 1882 Mexican-American individuals (60% female, mean age = 42.04, range = 18-97). Genetic correlations were calculated using a variance components approach between the cytokines TNF-α, IL-6 and IL-8, and Lifetime Suicide Attempt and Current Suicidal Ideation. The potentially confounding effects of sex and BMI were considered. Results: 159 individuals endorse a Lifetime Suicide Attempt. IL-8 and IL-6 shared significant genetic overlap with risk for suicide attempt (ρg = 0.49, pFDR = 7.67 × 10-03; ρg = 0.53, pFDR = 0.01), but for IL-6 this was attenuated when BMI was included as a covariate (ρg = 0.37, se = 0.23, pFDR = 0.12). Suicide attempts were significantly more common in females (pFDR = 0.01) and the genetic overlap between IL-8 and risk for suicide attempt was significant in females (ρg = 0.56, pFDR = 0.01), but not in males (ρg = 0.44, pFDR = 0.30). Discussion: These results demonstrate that: IL-8 shares genetic influences with risk for suicide attempt; females drove this effect; and BMI should be considered when assessing the association between IL-6 and suicide. This finding represents a significant advancement in knowledge by demonstrating that cytokine alterations are not simply a secondary manifestation of suicidal behavior, but rather, the pathophysiology of suicide attempts is, at least partly, underpinned by the same biological mechanisms responsible for regulating inflammatory response

The Genetic contribution to solving the cocktail-party problem

Communicating in everyday situations requires solving the cocktail-party problem, or segregating the acoustic mixture into its constituent sounds and attending to those of most interest. Humans show dramatic variation in this ability, leading some to experience real-world problems irrespective of whether they meet criteria for clinical hearing loss. Here, we estimated the genetic contribution to cocktail-party listening by measuring speech-reception thresholds (SRTs) in 425 people from large families and ranging in age from 18 to 91 years. Roughly half the variance of SRTs was explained by genes (h 2 = 0.567). The genetic correlation between SRTs and hearing thresholds (HTs) was medium (ρ G = 0.392), suggesting that the genetic factors influencing cocktail-party listening were partially distinct from those influencing sound sensitivity. Aging and socioeconomic status also strongly influenced SRTs. These findings may represent a first step toward identifying genes for hidden hearing loss, or hearing problems in people with normal HTs

Genome-wide significant linkage of schizophrenia-related neuroanatomical trait to 12q24

The insula and medial prefrontal cortex (mPFC) share functional, histological, transcriptional and developmental characteristics and they serve higher cognitive functions of theoretical relevance to schizophrenia and related disorders. Meta-analyses and multivariate analysis of structural magnetic resonance imaging (MRI) scans indicate that gray matter density and volume reductions in schizophrenia are the most consistent and pronounced in a network primarily composed of the insula and mPFC. We used source-based morphometry, a multivariate technique optimized for structural MRI, in a large sample of randomly ascertained pedigrees (N = 887) to derive an insula-mPFC component and to investigate its genetic determinants. Firstly, we replicated the insula-mPFC gray matter component as an independent source of gray matter variation in the general population, and verified its relevance to schizophrenia in an independent case-control sample. Secondly, we showed that the neuroanatomical variation defined by this component is largely determined by additive genetic variation (h2 = 0.59), and genome-wide linkage analysis resulted in a significant linkage peak at 12q24 (LOD = 3.76). This region has been of significant interest to psychiatric genetics as it contains the Darier’s disease locus and other proposed susceptibility genes (e.g. DAO, NOS1), and it has been linked to affective disorders and schizophrenia in multiple populations. Thus, in conjunction with previous clinical studies, our data imply that one or more psychiatric risk variants at 12q24 are co-inherited with reductions in mPFC and insula gray matter concentration

Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND)

Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD