GWAS in the SIGNAL/PHARE clinical cohort restricts the association between the FGFR2 locus and estrogen receptor status to HER2-negative breast cancer patients

International audienceGenetic polymorphisms are associated with breast cancer risk. Clinical and epidemiological observations suggest that clinical characteristics of breast cancer, such as estrogen receptor or HER2 status, are also influenced by hereditary factors. To identify genetic variants associated with pathological characteristics of breast cancer patients, a Genome Wide Association Study was performed in a cohort of 9365 women from the French nationwide SIGNAL/PHARE studies (NCT00381901/RECF1098). Strong association between the FGFR2 locus and ER status of breast cancer patients was observed (ER-positive n=6211, ER-negative n=2516; rs3135718 OR=1.34 p=5.46x10-12). This association was limited to patients with HER2-negative tumors (ER-positive n=4267, ER-negative n=1185; rs3135724 OR=1.85 p=1.16x10-11). The FGFR2 locus is known to be associated with breast cancer risk. This study provides sound evidence for an association between variants in the FGFR2 locus and ER status among breast cancer patients, particularly among patients with HER2-negative disease. This refinement of the association between FGFR2 variants and ER-status to HER2-negative disease provides novel insight to potential biological and clinical influence of genetic polymorphisms on breast tumors

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

Sex specific associations in genome wide association analysis of renal cell carcinoma.

Renal cell carcinoma (RCC) has an undisputed genetic component and a stable 2:1 male to female sex ratio in its incidence across populations, suggesting possible sexual dimorphism in its genetic susceptibility. We conducted the first sex-specific genome-wide association analysis of RCC for men (3227 cases, 4916 controls) and women (1992 cases, 3095 controls) of European ancestry from two RCC genome-wide scans and replicated the top findings using an additional series of men (2261 cases, 5852 controls) and women (1399 cases, 1575 controls) from two independent cohorts of European origin. Our study confirmed sex-specific associations for two known RCC risk loci at 14q24.2 (DPF3) and 2p21(EPAS1). We also identified two additional suggestive male-specific loci at 6q24.3 (SAMD5, male odds ratio (ORmale) = 0.83 [95% CI = 0.78-0.89], Pmale = 1.71 × 10-8 compared with female odds ratio (ORfemale) = 0.98 [95% CI = 0.90-1.07], Pfemale = 0.68) and 12q23.3 (intergenic, ORmale = 0.75 [95% CI = 0.68-0.83], Pmale = 1.59 × 10-8 compared with ORfemale = 0.93 [95% CI = 0.82-1.06], Pfemale = 0.21) that attained genome-wide significance in the joint meta-analysis. Herein, we provide evidence of sex-specific associations in RCC genetic susceptibility and advocate the necessity of larger genetic and genomic studies to unravel the endogenous causes of sex bias in sexually dimorphic traits and diseases like RCC

A major locus on chromosome 3p22 conferring predisposition to human herpesvirus 8 infection

International audienceInfection with human herpesvirus 8 (HHV-8), the etiological agent of Kaposi's sarcoma, has been shown to display strong familial aggregation, in countries in which HHV-8 infection is endemic. We investigated 40 large families (608 subjects aged one to 88 years) living in an isolated area of Cameroon in which HHV-8 is highly endemic. We performed a two-step genetic analysis for HHV-8 infection status (HHV-8+/HHV-8- determined by immunofluorescence) consisting of an initial segregation analysis followed by a model-based genome-wide linkage analysis. Overall HHV-8 seroprevalence was 60%, increasing with age. Segregation analysis provided strong evidence for a recessive major gene conferring predisposition to HHV-8 infection. This gene is predicted to have a major effect during childhood, with almost all homozygous predisposed subjects (∼7% of the population) becoming infected by the age of 10. Linkage analysis was carried out on the 15 most informative families, corresponding to 205 genotyped subjects. A single region on chromosome 3p22 was significantly linked to HHV-8 infection (LOD score=3.83, P=2.0 × 10(-5)). This study provides the first evidence that HHV-8 infection in children in endemic areas has a strong genetic basis involving at least one recessive major locus on chromosome 3p22

Prenyldiphosphate synthase, subunit 1 (PDSS1) and OH-benzoate polyprenyltransferase (COQ2) mutations in ubiquinone deficiency and oxidative phosphorylation disorders

Coenzyme Q(10) (CoQ(10)) plays a pivotal role in oxidative phosphorylation (OXPHOS), as it distributes electrons among the various dehydrogenases and the cytochrome segments of the respiratory chain. We have identified 2 novel inborn errors of CoQ(10) biosynthesis in 2 distinct families. In both cases, enzymologic studies showed that quinone-dependent OXPHOS activities were in the range of the lowest control values, while OXPHOS enzyme activities were normal. CoQ(10) deficiency was confirmed by restoration of normal OXPHOS activities after addition of quinone. A genome-wide search for homozygosity in family 1 identified a region of chromosome 10 encompassing the gene prenyldiphosphate synthase, subunit 1 (PDSS1), which encodes the human ortholog of the yeast COQ1 gene, a key enzyme of CoQ(10) synthesis. Sequencing of PDSS1 identified a homozygous nucleotide substitution modifying a conserved amino acid of the protein (D308E). In the second family, direct sequencing of OH-benzoate polyprenyltransferase (COQ2), the human ortholog of the yeast COQ2 gene, identified a single base pair frameshift deletion resulting in a premature stop codon (c.1198delT, N401fsX415). Transformation of yeast Δcoq1 and Δcoq2 strains by mutant yeast COQ1 and mutant human COQ2 genes, respectively, resulted in defective growth on respiratory medium, indicating that these mutations are indeed the cause of OXPHOS deficiency

A Novel Primary Immunodeficiency with Specific Natural-Killer Cell Deficiency Maps to the Centromeric Region of Chromosome 8

We describe four children with a novel primary immunodeficiency consisting of specific natural-killer (NK) cell deficiency and susceptibility to viral diseases. One child developed an Epstein-Barr virus–driven lymphoproliferative disorder; two others developed severe respiratory illnesses of probable viral etiology. The four patients are related and belong to a large inbred kindred of Irish nomadic descent, which suggests autosomal recessive inheritance of this defect. A genomewide scan identified a single 12-Mb region on chromosome 8p11.23-q11.21 that was linked to this immunodeficiency (maximum LOD score 4.51). The mapping of the disease-causing genomic region paves the way for the identification of a novel pathway governing NK cell differentiation in humans

Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia–associated epilepsy

International audienceDEP domain–containing 5 protein (DEPDC5) is a repressor of the recently recognized amino acid–sensing branch of the mTORC1 pathway. So far, its function in the brain remains largely unknown. Germline loss-of-function mutations in DEPDC5 have emerged as a major cause of familial refractory focal epilepsies, with case reports of sudden unexpected death in epilepsy (SUDEP). Remarkably, a fraction of patients also develop focal cortical dysplasia (FCD), a neurodevelopmental cortical malformation. We therefore hypothesized that a somatic second-hit mutation arising during brain development may support the focal nature of the dysplasia. Here, using postoperative human tissue, we provide the proof of concept that a biallelic 2-hit — brain somatic and germline — mutational mechanism in DEPDC5 causes focal epilepsy with FCD. We discovered a mutation gradient with a higher rate of mosaicism in the seizure-onset zone than in the surrounding epileptogenic zone. Furthermore, we demonstrate the causality of a Depdc5 brain mosaic inactivation using CRISPR-Cas9 editing and in utero electroporation in a mouse model recapitulating focal epilepsy with FCD and SUDEP-like events. We further unveil a key role of Depdc5 in shaping dendrite and spine morphology of excitatory neurons. This study reveals promising therapeutic avenues for treating drug-resistant focal epilepsies with mTORC1-targeting molecules

Layer myocardial strain is the most heritable echocardiographic trait

Abstract Aims Myocardial deformation assessed by strain analysis represents a significant advancement in our assessment of cardiac mechanics. However, whether this variable is genetically heritable or whether all/most of its variability is related to environmental factors is currently unknown. We sought to determine the heritability of echocardiographically determined cardiac mechanics indices in a population setting. Methods and results A total of 1357 initially healthy subjects (women 51.6%; 48.2 ± 14.1 years) were included in this study from 20-year follow-up after the fourth visit of the longitudinal familial STANISLAS cohort (Lorraine, France). Data were acquired using state-of-the-art cardiac ultrasound equipment, using acquisition and measurement protocols recommended by the EACVI (European Association of Cardiovascular Imaging)/ASE (American Society of Echocardiography)/Industry Task Force. Layer-specific global longitudinal strain (GLS) and global circumferential strain (full-wall, subendocardial, and subepicardial) and conventional structural and functional cardiac parameters and their potential heritability were assessed using restricted maximum likelihood analysis, with genetic relatedness matrix calculated from genome-wide association data. Indices of longitudinal/circumferential myocardial function and left ventricular (LV) ejection fraction had low heritability (ranging from 10% to 20%). Diastolic and standard LV function parameters had moderate heritability (ranging from 20% to 30%) except for end-systolic and end-diastolic volumes (30% and 45%, respectively). In contrast, global longitudinal subendocardial strain (GLSEndo)/global longitudinal subepicardial strain (GLSEpi) ratio had a high level of heritability (65%). Except for GLSEndo/GLSEpi ratio, a large percentage of variance remained unexplained (&amp;gt;50%). Conclusions In our population cohort, GLSEndo/GLSEpi ratio had a high level of heritability, whereas other classical and mechanical LV function parameters did not. Given the increasing recognition of GLSEndo/GLSEpi ratio as an early/sensitive imaging biomarker of systolic dysfunction, our results suggest the possible existence of individual genetic predispositions to myocardial decline. </jats:sec

GRID2 mutations span from congenital to mild adult-onset cerebellar ataxia

International audienceObjectives:In a large family of Algerian origin, we aimed to identify the genetic mutation segregating with simultaneous presence of adult-onset, paucisymptomatic, slowly progressive, cerebellar ataxia in 7 adults and congenital ataxia in 1 child, and then to assess the involvement of GRID2 mutations in 144 patients with congenital cerebellar ataxia.Methods:We used a combined approach of linkage analysis and whole-exome sequencing in one family, and a targeted gene panel sequencing approach in 144 congenital ataxias.Results:In the large family with spinocerebellar ataxia, we identified a missense mutation (c.1966C>G/p.Leu656Val) in the GRID2 gene, in a heterozygous state in adults, and in a homozygous state in one child with congenital ataxia, compatible with a semidominant transmission pattern. In 144 patients affected with congenital ataxia, we identified 2 missense de novo GRID2 mutations in 2 children (c.1960G>A/p.Ala654Thr, c.1961C>A/p.Ala654Asp). They affect the same amino acid as the previously described Lurcher mutation in mice; the variant in the large family concerns a nearby amino acid.Conclusions:In humans, GRID2 had only been involved in ataxia through complete loss-of-function mutations due to exon deletions. We report the first point mutations in this gene, with putative gain-of-function mechanisms, and a semidominant transmission as was observed in the Lurcher mice model. Of note, cerebellar ataxia is the core phenotype, but with variable severity ranging from very mild adult-onset to congenital-onset ataxias linked to both the heterozygous and homozygous state of the variant, and the position of the mutation

Heritability of a resting heart rate in a 20-year follow-up family cohort with GWAS data: Insights from the STANISLAS cohort

International audienceBACKGROUND:The association between resting heart rate (HR) and cardiovascular outcomes, especially heart failure, is now well established. However, whether HR is mainly an integrated marker of risk associated with other features, or rather a genetic origin risk marker, is still a matter for debate. Previous studies reported a heritability ranging from 14% to 65%.DESIGN:We assessed HR heritability in the STANISLAS family-study, based on the data of four visits performed over a 20-year period, and adjusted for most known confounding effects.METHODS:These analyses were conducted using a linear mixed model, adjusted on age, sex, tea or coffee consumption, beta-blocker use, physical activity, tobacco use, and alcohol consumption to estimate the variance captured by additive genetic effects, via average information restricted maximum likelihood analysis, with both self-reported pedigree and genetic relatedness matrix (GRM) calculated from genome-wide association study data.RESULTS:Based on the data of all visits, the HR heritability (h2) estimate was 23.2% with GRM and 24.5% with pedigree. However, we found a large heterogeneity of HR heritability estimations when restricting the analysis to each of the four visits (h2 from 19% to 39% using pedigree, and from 14% to 32% using GRM). Moreover, only a little part of variance was explained by the common household effect (<5%), and half of the variance remained unexplained.CONCLUSION:Using a comprehensive analysis based on a family cohort, including the data of multiple visits and GRM, we found that HR variability is about 25% from genetic origin, 25% from repeated measures and 50% remains unexplained