Rare Variants In Genes Research Articles

TRANSETHNIC META-ANALYSIS OF INTERACTIONS BETWEEN GENETICS AND EARLY-LIFE SOCIOECONOMIC CONTEXT ON COGNITION

Abstract Later-life cognitive function is influenced by genetics as well as early- and later-life socioeconomic context. However, few studies have examined the interaction between genetics and early childhood factors. Using gene-based tests (interaction sequence kernel association test [iSKAT]/iSKAT optimal unified test), we examined whether common and rare variants in 39 gene regions previously associated with cognitive performance, dementia, and related traits had an interaction with childhood socioeconomic context (parental education and financial strain) on memory performance or decline in European ancestry (EA, N = 10,468) and African ancestry (AA, N = 2,252) participants from the Health and Retirement Study. Of the 39 genes, 22 in EA and 19 in AA had nominally significant interactions with at least one childhood socioeconomic measure on memory performance and/or decline; however, only one, SLC24A4 x father’s education, remained significant after multiple testing correction (false discovery rate [FDR] < .05). In trans-ethnic meta-analysis, 2 genes interacted with childhood socioeconomic context: MS4A4A x mother’s education on memory performance, and SLC24A4 x father’s education on memory decline. Both interactions remained significant after adjusting for respondent’s own education, apolipoprotein-ε4 allele status, lifestyle factors, body mass index, and comorbidities. For both interactions in EA and AA, the genetic effect was stronger in participants with low parental education. Examination of common and rare variants in genes discovered through genome-wide association studies shows that childhood context may interact with gene regions to jointly impact later-life memory function and decline. Genetic effects may be more salient for those with lower childhood socioeconomic status.

Deciphering the host genetic factors conferring susceptibility to severe COVID-19 using exome sequencing.

The COVID-19 pandemic remains a significant public health concern despite the new vaccines and therapeutics. The clinical course of acute SARS-CoV-2 infection is highly variable and influenced by several factors related to the virus and the host. Numerous genetic studies, including candidate gene, exome, and genome sequencing studies, genome-wide association studies, and other omics efforts, have proposed various Mendelian and non-Mendelian associations with COVID-19 course. In this study, we conducted whole-exome sequencing on 90 unvaccinated patients from Turkey with no known comorbidities associated with severe COVID-19. Of these patients, 30 had severe, 30 had moderate, and 30 had mild/asymptomatic disease. We identified rare variants in genes associated with SARS-CoV-2 susceptibility and pathogenesis, with an emphasis on genes related to the regulation of inflammation, and discussed these in the context of the clinical course of the patients. In addition, we compared the frequencies of common variants between each group. Even though no variant remained statistically significant after correction for multiple testing, we observed that certain previously associated genes and variants showed significant associations before correction. Our study contributes to the existing literature regarding the genetic susceptibility to SARS-CoV-2. Future studies would be beneficial characterizing the host genetic properties in different populations.

Germline genetic variants in Turkish familial multiple myeloma/monoclonal gammopathy of undetermined significance cases.

Multiple myeloma (MM) is a haematological malignancy primarily affecting the elderly, with a striking male predilection and ethnic disparities in incidence. Familial predisposition to MM has long been recognized, but the genetic underpinnings remain elusive. This study aimed to investigate germline variants in Turkish families with recurrent MM cases. A total of 37 MM-affected families, comprising 77 individuals, were included. Targeted next-generation sequencing analysis yielded no previously reported rare variants. Whole exome sequencing analysis in 11 families identified rare disease-causing variants in various genes, some previously linked to familial MM and others not previously associated. Notably, genes involved in ubiquitination, V(D)J recombination and the PI3K/AKT/mTOR pathway were among those identified. Furthermore, a specific variant in BNIP1 (rs28199) was found in 13 patients across nine families, indicating its potential significance in MM pathogenesis. While this study sheds light on genetic variations in familial MM in Turkey, its limitations include sample size and the absence of invivo investigations. In conclusion, familial MM likely involves a polygenic inheritance pattern with rare, disease-causing variants in various genes, emphasizing the need for international collaborative efforts to unravel the intricate genetic basis of MM and develop targeted therapies.

Telomere length and cancer risk: finding Goldilocks.

Telomeres are the nucleoprotein complex at chromosome ends essential in genomic stability. Baseline telomere length (TL) is determined by rare and common germline genetic variants but shortens with age and is susceptible to certain environmental exposures. Cellular senescence or apoptosis are normally triggered when telomeres reach a critically short length, but cancer cells overcome these protective mechanisms and continue to divide despite chromosomal instability. Rare germline variants in telomere maintenance genes cause exceedingly short telomeres for age (< 1st percentile) and the telomere biology disorders, which are associated with elevated risks of bone marrow failure, myelodysplastic syndrome, acute myeloid leukemia, and squamous cell carcinoma of the head/neck and anogenital regions. Long telomeres due to rare germline variants in the same or different telomere maintenance genes are associated with elevated risks of other cancers, such as chronic lymphocytic leukemia or sarcoma. Early epidemiology studies of TL in the general population lacked reproducibility but new methods, including creation of a TL polygenic score using common variants, have found longer telomeres associated with excess risks of renal cell carcinoma, glioma, lung cancer, and others. It has become clear that when it comes to TL and cancer etiology, not too short, not too long, but "just right" telomeres are important in minimizing cancer risk.

Exome sequencing in 16 patients with pituitary stalk interruption syndrome: A monocentric study

Pituitary stalk interruption syndrome (PSIS) is a rare disorder characterized by an absent or ectopic posterior pituitary, absent or interrupted pituitary stalk and anterior pituitary hypoplasia on magnetic resonance imaging (MRI), as well in some cases a range of heterogeneous somatic anomalies. The triad can be incomplete. Here, we performed exome sequencing on 16 sporadic patients, aged 0.4 to 13.7 years diagnosed with isolated or complex PSIS. Growth hormone deficiency was isolated in 10 cases, or associated with thyrotropin deficiency in 6 others (isolated (2 cases), associated with adrenocorticotropin deficiency (1 case), gonadotropins deficiency (1 case), or multiple deficiencies (2 cases)). Additional phenotypic anomalies were present in six cases (37.5%) including four with ophthalmic disorders. In 13 patients variants were identified that may contribute to the phenotype. However, only a single individual carried a variant classified as pathogenic. This child presented with the typical clinical presentation of Okur-Chung neurodevelopmental syndrome due to a CSNK2A1 missense variant. We also identified variants in the holoprosencephaly associated genes GLI2 and PTCH1. A likely pathogenic novel splice site variant in the GLI2 gene was observed in a child with PSIS and megacisterna magna. In the remaining 11 cases 26 variants in genes associated with pituitary development or function were identified and were classified of unknown significance. Compared with syndromic forms the diagnostic yield in the isolated forms of PSIS is low. Although we identified rare or novel missense variants in several hypogonadotropic hypogonadism genes (e.g. FGF17, HS6ST1, KISS1R, CHD7, IL17RD) definitively linking them to the PSIS phenotype is premature. A major challenge remains to identify pathogenic variants in cases with isolated PSIS.

Identification of rare coding variants associated with Alzheimer’s disease.

AbstractBackgroundPrevious whole exome sequencing (WES) studies of Alzheimer’s disease (AD) have identified genome‐wide significant associations with rare variants in several novel genes and highlighted the need for investigations in larger samples. We combined WES and whole genome sequencing (WGS) data assembled by the Alzheimer Disease Sequencing Project (ADSP) to increase the power for detecting associations of AD with rare variants in gene coding regions.MethodWe developed an efficient computational pipeline to perform both pre‐merging and post‐merging genotype, variant and sample‐level quality control (QC) on WGS data containing 16,905 individuals and WES data for 20,504 individuals. The resultant sample included participants from European (EA, 11,279 AD cases, 8,924 controls), African American (AA, 2,757 AD cases, 4,336 controls), and Caribbean Hispanic (CH 1,438 AD cases, 3,256 controls) ancestries. We employed GENESIS to test association of AD with 250,465 bi‐allelic QC’d variants using a logistic model including covariates for age, sex, exome capture kit, read length, and ancestry principal components (PCs).ResultIn the total sample, variants from APOE and other known AD genes including SORL1 (P = 5.30×10‐7), NECTIN2 (P = 6.94×10‐7), and TREM2 R47H (P = 2.34×10‐13) crossed or neared the study‐wide significance (SWS) threshold of P = 2.00×10‐7 (0.05/250,465). SWS or borderline significant associations were also found with variants in several novel loci including TKTL2 (P = 2.35×10‐8), D2HGDH, (P = 1.09×10‐7), CECR1 (P = 4.02×10‐7), PDHA2 (P = 2.76×10‐7), GOLGA1 (P = 1.72×10‐7), CYLD (P = 1.84×10‐7), and RP11‐243M5.4 (P = 1.37×10‐7). PSEN1 missense mutation G206A (rs63750082) previously associated with early onset AD in the CH group, was significantly associated with late onset AD in the same population (P = 1.58×10‐13). SWS association of AD with APOE was observed in all groups. Significant associations were also observed with variants in SERPINB8 (P = 3.77×10‐9) and FAM171A (P = 7.20×10‐7) in EAs and TLR4 (P = 4.58×10‐7) in CH. Associations with several top‐ranked variants were replicated in the Alzheimer’s Disease Genetics Consortium GWAS dataset that were imputed using the TOPMed reference panel and ADSP 5K WGS dataset.ConclusionWe demonstrated that merging WGS and WES datasets can increase power to detect associations with rare coding variants in genes including ones previously implicated in AD (CYLD and TLR4) and early‐onset stroke (CECR1).

Whole‐exome sequencing of a Portuguese cohort of early‐onset Alzheimer’s disease implicates X‐linked lysosomal gene GLA

AbstractBackgroundCerebrovascular disease is a common comorbidity in patients with Alzheimer’s disease (AD) and other dementias. Accumulating evidence indicates that dysfunction of the cerebral vasculature and AD neuropathology interact in multiple ways. In fact, some studies have associated common variants in COL4A1 and rare variants in HTRA1, NOTCH3, COL4A1, and CST3 with AD pathogenesis.We aimed to identify rare genetic variants in genes associated with monogenic small vessel disease in in a cohort of Portuguese early‐onset AD patients.MethodWe performed whole‐exome sequencing in a cohort of 104 thoroughly studied patients with early‐onset AD, without known pathogenic variants in the genes associated with AD or frontotemporal dementia. In these patients, we searched for rare (MAF&lt;0.001) non‐synonymous variants in genes associated with small vessel disease: NOTCH3, HTRA1, COL4A1, COL4A2, CSTA, GLA and TREX1.ResultIn total, we found 12 rare variants in 18 patients. We found 3 male AD patients with a pathogenic GLA variant. We found other rare variants in NOTCH3, COL4A2 and HTRA1. Of the 3 patients carrying a GLA variant, one had a neuropathological study confirming the diagnosis of AD . This individual also revealed Fabry disease pathology in the hippocampal formation (CA1 to CA4 and subiculum).ConclusionWe found several rare variants on the genes of interest in our cohort. We provide evidence supporting the pathogenicity of the GLA variant. We show that 3 carriers of this variant, without other probable genetic cause responsible for the disease, developed early‐onset AD. One of those cases had post‐mortem confirmation of the diagnosis. We further show the localization of Fabry pathology in several areas that are vulnerable in AD. This poses the question of the variant’s possible role in AD pathogenesis.

CSF ADAM10 levels in AD patients in relationship to ADAM10 gene variants

AbstractBackgroundThe disintegrin metalloproteinase 10 (ADAM10) is the main α‐secretase acting in the non‐amyloidogenic processing of APP. Some ADAM10 gene variants (Q170H, R181G) have been associated with higher susceptibility to develop late‐onset AD and have been shown to promote AD‐type changes in mice models. We tested the hypothesis that some ADAM10 rare variants could increase the risk for AD through conferring an earlier age‐related downregulation of a‐secretase activity.Method ADAM10 gene was sequenced in 103 AD cases (78% with family history) with positive CSF biomarkers, and 96 cognitively preserved nonagenarians. ADAM10 in CSF of the AD cases was analyzed by means of ELISA (total levels) and western blot (segregated by isoforms of 50 kDa, 55 kDa, and 80 kDa) in comparison with controls and non‐AD dementia cases. We examined whether there was an increase of rare gene variants (MAF &lt; 0.01) in the AD group and their potential association with lowers CSF protein levels.ResultRare variants were found in 15,5% of AD cases (in 23% of early‐onset versus 7,8% in late‐onset, p = 0.058) and in 12,5% of nonagenarians, and several of them were exclusive of the group. However, all were intronic variants except the Q170H change found in three AD cases and one nonagenarian. The SNP rs74016945 (3’UTR), with MAF close to 0.01, was found in 6% of the nonagenarians (OR 0.146, Fisher exact test p = 0.057). ELISA ADAM10 levels were not significantly different comparing AD cases with controls, carriers of rare variants versus non‐carriers, and did not differ consistently according to age at onset or APOE genotype. The three ADAM10 species were also similar in AD cases and controls, and did not differ according to genetic variants or age at onset.ConclusionRare ADAM10 exonic variants are uncommon in AD cases and the presence of rare intronic variants (more frequent in early versus late‐onset cases) is not associated with decreased ADAM10 levels in CSF.

A Rare and Unusual Case of Ataxia Telangiectasia with Cervical Dystonia from India

We reported a rare and unusual case ATM gene variant responsible of familial Ataxia-Telangiectasia (A-T) with cervical dystonia rather than ataxia as hall mark clinical manifestations in 18-year-old male patient from India. Patient was presented with clinical indications of neck rotatory movements in the last 2 years. Initially intermittent, slowly become constant with more backwards turning and painful movements with severe disability. Examination findings revealed no conjunctival telangiectasia and neurological examination findings suggestive of cervical dystonia with severe retro collis. The patient has a family history of dystonia, his sister started noticing involuntary neck movement in the last 1.5 years with gradual progression. Her physical examination revealed no evidence of conjunctival lesions and neurological examination suggestive of cervical dystonia with lateral collis. MRI findings of patient were normal. Both the patient and her sister are siblings of a consanguineous product. Patient has been referred for whole exome sequencing. The exome data analysis identified a novel homozygous missense variant c.5751A&gt;T, p.Arg1917Ser (chr11:108307973A&gt;T) in ATM gene responsible for familial A-T with cervical dystonia without chorea as hall mark clinical manifestations. In conclusion, to the best of our literature knowledge this is the rare and unusual case from India wherein we are reporting a novel homozygous missense variant c.5751A&gt;T, p.Arg1917Ser (chr11:108307973A&gt;T) in ATM gene responsible for familial A-T with cervical dystonia rather than ataxia as hall mark clinical manifestations affecting both brother and sister in the same family. Thus, early onset of cervical dystonia should be taken into account as a key characteristic of variant A-T, which can manifest without general ataxia and may cause adults with primary dystonia to receive an incorrect diagnosis.

A pharmacogenetic study of perampanel: association between rare variants of glutamate receptor genes and outcomes

Introduction: The selection of antiseizure medication usually requires a trial-and-error process. Our goal is to investigate whether genetic markers can predict the outcome of perampanel (PER) use in patients with epilepsy.Method: The studied participants were selected from our previous epilepsy genetics studies where whole exome sequencing was available. We reviewed the medical records of epilepsy patients older than 20 years old treated with PER. The outcome of PER treatment included the response to PER, the occurrence of any adverse drug reaction (ADR), the presence of behavior ADR, and the ability to adhere to PER for more than 1 year. We investigated the association between the rare variants of the glutamate receptor genes and the outcomes of PER use.Result: A total of 83 patients were collected. The gene group burden analysis showed that enriched genetic variants of the glutamate receptor gene group were statistically significantly associated with the occurrence of ADR, while the glutamate ionotropic receptor delta type subunit had a nominal association with the occurrence of ADR. The gene collapse analysis found that GRID1 had a nominal association with the occurrence of ADR and GRIN3A had a nominal association with the occurrence of behavior ADR. However, these nominal associations did not remain statistically significant once adjusted for multiple testing.Discussion: We found that enriched rare genetic variants of the glutamate receptor genes were associated with the occurrence of ADR in patients taking PER. In the future, combining the results of various pharmacogenetic studies may lead to the development of prediction tools for the outcome of antiseizure medications.

Assortative mating and parental genetic relatedness contribute to the pathogenicity of variably expressive variants

We examined more than 97,000 families from four neurodevelopmental disease cohorts and the UK Biobank to identify phenotypic and genetic patterns in parents contributing to neurodevelopmental disease risk in children. We identified within- and cross-disorder correlations between six phenotypes in parents and children, such as obsessive-compulsive disorder (R= 0.32-0.38, p<10-126). We also found that measures of sub-clinical autism features in parents are associated with several autism severity measures in children, including biparental mean Social Responsiveness Scale scores and proband Repetitive Behaviors Scale scores (regression coefficient= 0.14, p=3.38×10-4). We further describe patterns of phenotypic similarity between spouses, where spouses show correlations for six neurological and psychiatric phenotypes, including a within-disorder correlation for depression (R= 0.24-0.68, p<0.001) and a cross-disorder correlation between anxiety and bipolar disorder (R= 0.09-0.22, p<10-92). Using a simulated population, we also found that assortative mating can lead to increases in disease liability over generations and the appearance of "genetic anticipation" in families carrying rare variants. We identified several families in a neurodevelopmental disease cohort where the proband inherited multiple rare variants in disease-associated genes from each of their affected parents. We further identified parental relatedness as a risk factor for neurodevelopmental disorders through its inverse relationship with variant pathogenicity and propose that parental relatedness modulates disease risk by increasing genome-wide homozygosity in children (R= 0.05-0.26, p<0.05). Our results highlight the utility of assessing parent phenotypes and genotypes toward predicting features in children who carry rare variably expressive variants and implicate assortative mating as a risk factor for increased disease severity in these families.

Implementation of a prospective screening strategy to identify adults with a telomere biology disorder among those undergoing lung transplant evaluation for interstitial lung disease

IntroductionPatients with interstitial lung disease (ILD) secondary to telomere biology disorders (TBD) experience increased morbidity after lung transplantation. Identifying patients with TBD may allow for personalized management to facilitate better outcomes. However, establishing a TBD diagnosis in adults is challenging. MethodsA TBD screening questionnaire was introduced prospectively into the lung transplant evaluation. Patients with ILD screening positive were referred for comprehensive TBD phenotyping and concurrent telomere length measurement and germline genetic testing. ResultsOf 98 patients, 32 (33%) screened positive. Eight patients (8% of total; 25% of patients with a positive screen) met strict TBD diagnostic criteria, requiring either critically short lymphocyte telomeres (<1st percentile) (n = 4), a pathogenic variant in a TBD-associated gene (n = 1), or both (n = 3) along with a TBD clinical phenotype. Additional patients not meeting strict diagnostic criteria had histories consistent with TBD along with telomere lengths <10th percentile and/or rare variants in TBD-associated genes, highlighting a critical need to refine TBD diagnostic criteria for this patient population. ConclusionA TBD phenotype screening questionnaire in patients with ILD undergoing lung transplant evaluation has a diagnostic yield of 25%. Additional gene discovery, rare variant functional testing, and refined TBD diagnostic criteria are needed to realize the maximum benefit of testing for TBD in patients undergoing lung transplantation.

Genomics of iron refractory iron deficiency anemia phenotype reveals a spectrum of novel pathogenic biallelic and monoallelic TMPRSS6 variants and rare overlapping disorders

The study highlights genomic findings in a series of 13 IRIDA phenotype cases. All had microcytic hypochromic anemia with suboptimal oral iron response to two different oral iron preparations at 4–6 weeks and low-normal ferritin, low transferrin saturation, and inappropriately high hepcidin. Targeted NGS on a 26-gene iron panel revealed pathogenic TMPRSS6 variants in 5/13 (38 %) cases. In addition, 2 (15 %) cases revealed rare SMAD4 and TBXAS1 gene variants that can present with refractory anemia but were consistent with diagnosis of hereditary hemorrhagic telangiectasia and Ghosal hematodiaphyseal dysplasia respectively.

The burden of rare variants in DPYS gene is a novel predictor of the risk of developing severe fluoropyrimidine-related toxicity

BackgroundDespite a growing number of publications highlighting the potential impact on the therapy outcome, rare genetic variants (minor allele frequency < 1%) in genes associated to drug adsorption, distribution, metabolism, and elimination are poorly studied. Previously, rare germline DPYD missense variants were shown to identify a subset of fluoropyrimidine-treated patients at high risk for severe toxicity. Here, we investigate the impact of rare genetic variants in a panel of 54 other fluoropyrimidine-related genes on the risk of severe toxicity.MethodsThe coding sequence and untranslated regions of 54 genes related to fluoropyrimidine pharmacokinetics/pharmacodynamics were analyzed by next-generation sequencing in 120 patients developing grade 3–5 toxicity (NCI-CTC vs3.0) and 104 matched controls. Sequence Kernel Association Test (SKAT) analysis was used to select genes with a burden of genetic variants significantly associated with risk of severe toxicity. The statistical association of common and rare genetic variants in selected genes was further investigated. The functional impact of genetic variants was assessed using two different in silico prediction tools (Predict2SNP; ADME Prediction Framework).ResultsSKAT analysis highlighted DPYS and PPARD as genes with a genetic mutational burden significantly associated with risk of severe fluoropyrimidine-related toxicity (Bonferroni adjusted P = 0.024 and P = 0.039, respectively). Looking more closely at allele frequency, the burden of rare DPYS variants was significantly higher in patients with toxicity compared with controls (P = 0.047, Mann–Whitney test). Carrying at least one rare DPYS variant was associated with an approximately fourfold higher risk of severe cumulative (OR = 4.08, P = 0.030) and acute (OR = 4.21, P = 0.082) toxicity. The burden of PPARD rare genetic variants was not significantly related to toxicity. Some common variants with predictive value in DPYS and PPARD were also identified: DPYS rs143004875-T and PPARD rs2016520-T variants predicted an increased risk of severe cumulative (P = 0.002 and P = 0.001, respectively) and acute (P = 0.005 and P = 0.0001, respectively) toxicity.ConclusionThis work demonstrated that the rare mutational burden of DPYS, a gene strictly cooperating with DPYD in the catabolic pathway of fluoropyrimidines, is a promising pharmacogenetic marker for precision dosing of fluoropyrimidines. Additionally, some common genetic polymorphisms in DPYS and PPARD were identified as promising predictive markers that warrant further investigation.

Genome-wide association meta-analysis of 5,864 individuals highlights 25 new loci implicated in the pathogenesis of cancer therapy-related cardiac dysfunction

Abstract Background Cancer therapy-related cardiac dysfunction, which commonly includes varying degrees of asymptomatic ventricular dysfunction and/or heart failure, is the main adverse effect of anticancer therapy. The mechanism by which it develops is still quite uncertain. In recent years several genetic association studies have identified common genetic variants associated with cardiotoxicity in genes related to DNA damage, drug transportation and metabolism, antioxidant mechanism, sarcomere dysfunction and impaired iron metabolism, but the evidence is still limited. Rare variants in familial cardiomyopathies genes have also been identified. Purpose This uncertainly requires larger studies to identify genetic variants allowing to predict the risk of cardiotoxicity. In this sense, we carry out a genome-wide association meta-analysis to identify genetic variants associated with cancer therapy-related cardiac dysfunction. The development of a risk predictor model combining clinical and genetic factors would make it possible to anticipate the adverse effects of this therapy. Methods Genome wide meta-analysis was performed with a total of 594 patients from the CARDIOTOX registry and 3545 healthy individuals from the National DNA Bank, together with three previously published independent cohorts with 1446, 227 and 52 individuals receiving cancer therapy. Patients were classified with different cardiotoxicity degrees based on the CARDIOTOX registry and exhaustive clinical information was obtained from medical records. The study was ethically approved by local institutional review boards and all participants provided written informed consent. DNA samples were genotyped and imputed to perform a GWAS meta-analysis for case-control (n=5864) and extreme phenotypes (n=5317) looking for genetic variants that predispose to developing cancer therapy-related cardiac dysfunction. A functional characterization of the significant loci was performed by colocalization with eQTLs. Results The case-control analysis showed 17 loci that achieved suggestive significance (&amp;lt; P=1 x10-5) (Figure 1). The rs6765460, an intergenic variant between TPRG1 and TP63 genes, had the strongest relationship with the development of cardiotoxicity (P=1.89x10-7). The extreme phenotypes analysis showed additional 8 loci that achieved suggestive significance. The rs12904266, an intron variant of SLCO3A1, had the strongest relationship with severe cardiotoxicity (P=3.20E-07). eQTLs colocalization of the significant loci revealed association with genes involved in the mitochondria, inflammation, immune system, and fibrosis. Conclusions Our GWAS meta-analysis identified 25 novel genetic variants that may be associated with cancer therapy-related cardiac dysfunction. Genotyping of these markers could be considered in a genetic risk score which, together with the already known clinical risk factors, would improve the cardiotoxicity prediction in cardio-oncology units.Figure 1.Miami plot with P values

Genetics of human longevity: From variants to genes to pathways.

The current increase in lifespan without an equivalent increase in healthspan poses a grave challenge to the healthcare system and a severe burden on society. However, some individuals seem to be able to live a long and healthy life without the occurrence of major debilitating chronic diseases, and part of this trait seems to be hidden in their genome. In this review, we discuss the findings from studies on the genetic component of human longevity and the main challenges accompanying these studies. We subsequently focus on results from genetic studies in model organisms and comparative genomic approaches to highlight the most important conserved longevity-associated pathways. By combining the results from studies using these different approaches, we conclude that only five main pathways have been consistently linked to longevity, namely (1) insulin/insulin-like growth factor 1 signalling, (2) DNA-damage response and repair, (3) immune function, (4) cholesterol metabolism and (5) telomere maintenance. As our current approaches to study the relevance of these pathways in humans are limited, we suggest that future studies on the genetics of human longevity should focus on the identification and functional characterization of rare genetic variants in genes involved in these pathways.

Gene-based association study of rare variants in children of diverse ancestries implicates TNFRSF21 in the development of allergic asthma

BackgroundMost genetic studies of asthma and allergy have focused on common variation in individuals primarily of European ancestry. Studying the role of rare variation in quantitative phenotypes and in asthma phenotypes in populations of diverse ancestries can provide additional, important insights into the development of these traits. ObjectiveThe goal of this study was to examine the contribution of rare variants to different asthma- or allergy-associated quantitative traits in children with diverse ancestries and explore their role in asthma phenotypes. MethodsWe examined whole-genome sequencing (WGS) data from children participants in longitudinal studies of asthma (n=1,035; parent-identified as 67% Black and 25% Hispanic) to identify rare variants (minor allele frequency < 0.01). We assigned variants to genes and tested for associations using an omnibus variant-set test between each of 24,902 genes and eight asthma-associated quantitative traits. Combining our results with external data on predicted gene expression in humans and mouse knockout studies, three candidate genes were identified. A burden of rare variants in each gene and in a combined 3-gene score was tested for its associations with clinical phenotypes of asthma. Finally, published single cell gene expression data in lower airway mucosal cells after allergen challenge was used to assess transcriptional responses to allergen. ResultsRare variants in USF1 were significantly associated with blood neutrophil count (p=2.18x10-7); rare variants in TNFRSF21 with total IgE (p=6.47x10-6) and PIK3R6 with eosinophil count (p=4.10x10-5) reached suggestive significance. These three findings were supported by independent data from human and mouse studies. A burden of rare variants in TNFRSF21 and in a 3-gene score were associated with allergy-related phenotypes in cohorts of children with mild and severe asthma. Furthermore, TNFRSF21 was significantly upregulated in bronchial basal epithelial cells from adults with allergic asthma but not in adults with allergies (but not asthma) after allergen challenge. ConclusionWe report novel associations between rare variants in genes and allergic and inflammatory phenotypes in children with diverse ancestries, highlighting TNFRSF21 as contributing to the development of allergic asthma.

Abstract 14472: Identifying the Genetic Determinants of Early Heart Failure in Patients With Congenital Heart Disease

Introduction: Heart failure (HF) is the most common cause of death in patients with congenital heart disease (CHD). Evidence suggests genetics play a role in HF predisposition. In particular, variants in cardiomyopathy-associated genes may be associated with HF and early mortality in CHD populations. Goal: Our goal is to leverage a large, well-curated, population-based cohort of individuals with CHD in North Carolina (NC) to determine the genetic underpinnings of HF in CHD. Hypothesis: We hypothesize that rare variants in cardiomyopathy-associated genes will be over-represented in CHD patients with HF compared to patients without HF. Methods: Patients were enrolled with inclusion criteria of 1) presence of CHD, 2) 2+ cardiac evaluations. Whole blood was collected for exome sequencing (ES). The presence of HF was defined as death, cardiac transplantation or listed for cardiac transplantation, VAD placement, ECMO cannulation, EF ≤ 40% on 2 images, or diagnosis of HF by a cardiologist and taking at least 1 HF medication. ES data was filtered for variants in cardiomyopathy-associated genes. Results: We have established NC-DEFINE: Determining the Genetic Basis of Heart Failure in Patients with CHD in NC, a prospectively enrolled cohort of patients with CHD for which ES data are available. We enrolled 138 CHD patients (mean age at enrollment [std dev]: 7.44+/-11.89 years; 40.6% female, 1.4% Asian, 23.9% Black, 6.5% Hispanic). About half (52.9%) have single ventricle physiology and 26% have HF. In a pilot ES cohort of 48 patients, there was an average of 524.2 variants/patient in cardiomyopathy genes of interest. After filtering out common and tolerated variants, 8 loss-of-function and 28 missense variants were identified and interpreted using ACMG criteria. Likely pathogenic or pathogenic (LPP) variants were found in 26.9% (7/26) of HF patients and 9.1% (2/22) of non-HF patients ( p =0.15). The RR for having a cardiomyopathy-associated LPP variant and developing HF in the setting of CHD was 1.60 (95% CI 1.0-2.57). Conclusions: We have established NC-DEFINE, a novel prospectively enrolled CHD cohort, to define the genetic architecture of HF in CHD. In a pilot ES cohort, we found enrichment of rare, LPP variants in cardiomyopathy-associated genes in patients with HF.

Abstract 15689: Ablation for Atrial Fibrillation in Patients With Rare Pathogenic Variants in Cardiomyopathy and Arrhythmia Genes

Introduction: Patients with rare, pathogenic cardiomyopathy (CM) and arrhythmia variants can present with atrial fibrillation (AF), with or without overt ventricular involvement. The efficacy of AF ablation in these patients is unknown. Research Questions/Hypothesis: To test the hypotheses that: 1) patients with a pathogenic variant in any CM or arrhythmia gene have a higher risk of recurrence following AF ablation, and 2) patients with a pathogenic variant associated with a specific gene group (arrhythmogenic left ventricular CM [ALVC], arrhythmogenic right ventricular CM [ARVC], dilated CM [DCM], hypertrophic CM [HCM], or a channelopathy) have a higher risk of recurrence. Methods: We performed a prospective observational cohort study in participants referred for AF catheter ablation who underwent whole exome sequencing. Our primary outcome was AF recurrence, defined as &gt;30 seconds of AF, atrial flutter, or atrial tachycardia that occurred at least 90 days after AF ablation. Results: Among 1,366 participants, 109 (8.0%) had a pathogenic or likely-pathogenic (P/LP) variant in a CM or arrhythmia gene. In multivariable analysis, presence of a P/LP variant in any gene was not significantly associated with recurrence (HR 1.15 (0.84-1.60), p=0.53, Figure 1A ). When analyzed according to gene group, P/LP variants in the ALVC gene group, predominantly LMNA , were associated with increased recurrence (N=10; HR 3.75 (1.84-7.63), p&lt;0.001), compared to those in the ARVC gene group (N=6; HR 1.97 (0.62-6.27), p=0.25), DCM gene group (N=50; HR 0.98 (0.59-1.63), p=0.94), HCM gene group (N=33; HR 1.28 (0.76-2.17), p=0.35), and channelopathy gene group (N=17; HR 0.58 (0.21-1.56), p=0.28), as shown in Figure 1B, 1C . Conclusions: Our results support the continued use of AF ablation for most patients with rare pathogenic CM or arrhythmia variants, including TTN . However, patients with ALVC variants, such as in LMNA , may be at a significantly higher risk for arrhythmia recurrence.

Molecular genetics of neuropsychiatric illness: some musings.

Research into the genetic underpinnings of neuropsychiatric illness has occurred at many levels. As more information accumulates, it appears that many approaches may each offer their unique perspective. The search for low penetrance and common variants, that may mediate risk, has necessitated the formation of many international consortia, to pool resources, and achieve the large sample sizes needed to discover these variants. There has been the parallel development of statistical methods to analyse large datasets and present summary statistics which allows data comparison across studies. Even so, the results of studies on well-characterised clinical datasets of modest sizes can be enlightening and provide important clues to understanding these complex disorders. We describe the use of common variants, at multiallelic loci like TOMM40 and APOE to study dementia, weighted genetic risk scores for alcohol-induced liver cirrhosis and whole exome sequencing to identify rare variants in genes like PLA2G6 in familial psychoses and schizophrenia in our Indian population.