Role Of Rare Genetic Variants Research Articles

Exome sequencing identifies genes associated with sleep-related traits.

Sleep is vital for human health and has a moderate heritability. Previous genome-wide association studies have limitations in capturing the role of rare genetic variants in sleep-related traits. Here we conducted a large-scale exome-wide association study of eight sleep-related traits (sleep duration, insomnia symptoms, chronotype, daytime sleepiness, daytime napping, ease of getting up in the morning, snoring and sleep apnoea) among 450,000 participants from UK Biobank. We identified 22 new genes associated with chronotype (ADGRL4, COL6A3, CLK4 and KRTAP3-3), daytime sleepiness (ST3GAL1 and ANKRD12), daytime napping (PLEKHM1, ANKRD12 and ZBTB21), snoring (WDR59) and sleep apnoea (13 genes). Notably, 20 of these genes were confirmed to be significantly associated with sleep disorders in the FinnGen cohort. Enrichment analysis revealed that these discovered genes were enriched in circadian rhythm and central nervous system neurons. Phenotypic association analysis showed that ANKRD12 was associated with cognition and inflammatory traits. Our results demonstrate the value of large-scale whole-exome analysis in understanding the genetic architecture of sleep-related traits and potential biological mechanisms.

Common and rare variant associations with latent traits underlying depression, bipolar disorder, and schizophrenia

Genetic studies in psychiatry have primarily focused on the effects of common genetic variants, but few have investigated the role of rare genetic variants, particularly for major depression. In order to explore the role of rare variants in the gap between estimates of single nucleotide polymorphism (SNP) heritability and twin study heritability, we examined the contribution of common and rare genetic variants to latent traits underlying psychiatric disorders using high-quality imputed genotype data from the UK Biobank. Using a pre-registered analysis, we used items from the UK Biobank Mental Health Questionnaire relevant to three psychiatric disorders: major depression (N = 134,463), bipolar disorder (N = 117,376) and schizophrenia (N = 130,013) and identified a general hierarchical factor for each that described participants’ responses. We calculated participants’ scores on these latent traits and conducted single-variant genetic association testing (MAF > 0.05%), gene-based burden testing and pathway association testing associations with these latent traits. We tested for enrichment of rare variants (MAF 0.05–1%) in genes that had been previously identified by common variant genome-wide association studies, and genes previously associated with Mendelian disorders having relevant symptoms. We found moderate genetic correlations between the latent traits in our study and case–control phenotypes in previous genome-wide association studies, and identified one common genetic variant (rs72657988, minor allele frequency = 8.23%, p = 1.01 × 10−9) associated with the general factor of schizophrenia, but no other single variants, genes or pathways passed significance thresholds in this analysis, and we did not find enrichment in previously identified genes.

Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits.

Despite increasing evidence of a role of rare genetic variation in the risk of Alzheimer's disease (AD), limited attention has been paid to its contribution to AD-related biomarker traits indicative of AD-relevant pathophysiological processes. We performed whole-exome gene-based rare-variant association studies (RVASs) of 17 AD-related traits on whole-exome sequencing (WES) data generated in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study (n=450) and whole-genome sequencing (WGS) data from ADNI (n=808). Mutation screening revealed a novel probably pathogenic mutation (PSEN1 p.Leu232Phe). Gene-based RVAS revealed the exome-wide significant contribution of rare coding variation in RBKS and OR7A10 to cognitive performance and protection against left hippocampal atrophy, respectively. The identification of these novel gene-trait associations offers new perspectives into the role of rare coding variation in the distinct pathophysiological processes culminating in AD, which may lead to identification of novel therapeutic and diagnostic targets.

Evaluating the role of rare genetic variation in sleep duration

ObjectivesTo explore the roles of rare and high-impact variants in sleep duration. DesignBased on the recently released UK Biobank 200k exome dataset, an exome-wide association study was conducted to detect rare variants (minor allele frequency <0.01) contributing to sleep duration. Variant annotations were performed by the software tool ANNOVAR. Gene-based burden tests of sleep duration were conducted by the SKAT R-package. After quality control, 137,047 subjects were included in this study. CAUSALdb database was used to explore the related mental traits of identified genes. ResultsWe detected 730,572 variants with MAF < 1%, including 3873 frameshift variants, 3977 nonframeshift variants, 449,632 nonsynonymous variants, 1293 startloss variants, 10,254 stopgain variants, 413 stoploss variants, 261,130 synonymous variants, and 3102 variants are annotated as unknown. The burden test of exonic variants detected two exome-wide significant associations for sleep duration including TMIE at 3p21.31 (PBonferroni adjusted = 0.015) and ZIC2 at 13q32.3 (PBonferroni adjusted = 0.047). There are only nonsynonymous contained in TMIE; as for ZIC2, we detected 2 annotations of variants: nonsynonymous (PBonferroni adjusted =2.04 × 10−4) and nonframeshift (PBonferroni adjusted =0.85). TMIE and ZIC2 were reported to be associated with several mental traits, such as chronotype, depression, and brain natriuretic peptide in published study. ConclusionThis study reported 2 novel candidate genes for a sleep duration, supporting the roles of rare genetic variants in the regulation of sleep duration.

Whole-genome sequencing analysis of clozapine-induced myocarditis.

One of the concerns limiting the use of clozapine in schizophrenia treatment is the risk of rare but potentially fatal myocarditis. Our previous genome-wide association study and human leucocyte antigen analyses identified putative loci associated with clozapine-induced myocarditis. However, the contribution of DNA variation in cytochrome P450 genes, copy number variants and rare deleterious variants have not been investigated. We explored these unexplored classes of DNA variation using whole-genome sequencing data from 25 cases with clozapine-induced myocarditis and 25 demographically-matched clozapine-tolerant control subjects. We identified 15 genes based on rare variant gene-burden analysis (MLLT6, CADPS, TACC2, L3MBTL4, NPY, SLC25A21, PARVB, GPR179, ACAD9, NOL8, C5orf33, FAM127A, AFDN, SLC6A11, PXDN) nominally associated (p < 0.05) with clozapine-induced myocarditis. Of these genes, 13 were expressed in human myocardial tissue. Although independent replication of these findings is required, our study provides preliminary insights into the potential role of rare genetic variants in susceptibility to clozapine-induced myocarditis.

Whole-exome sequencing reveals a role of HTRA1 and EGFL8 in brain white matter hyperintensities.

White matter hyperintensities (WMH) are among the most common radiological abnormalities in the ageing population and an established risk factor for stroke and dementia. While common variant association studies have revealed multiple genetic loci with an influence on their volume, the contribution of rare variants to the WMH burden in the general population remains largely unexplored. We conducted a comprehensive analysis of this burden in the UK Biobank using publicly available whole-exome sequencing data (n up to 17 830) and found a splice-site variant in GBE1, encoding 1,4-alpha-glucan branching enzyme 1, to be associated with lower white matter burden on an exome-wide level [c.691+2T>C, β = -0.74, standard error (SE) = 0.13, P = 9.7 × 10-9]. Applying whole-exome gene-based burden tests, we found damaging missense and loss-of-function variants in HTRA1 (frequency of 1 in 275 in the UK Biobank population) to associate with an increased WMH volume (P = 5.5 × 10-6, false discovery rate = 0.04). HTRA1 encodes a secreted serine protease implicated in familial forms of small vessel disease. Domain-specific burden tests revealed that the association with WMH volume was restricted to rare variants in the protease domain (amino acids 204-364; β = 0.79, SE = 0.14, P = 9.4 × 10-8). The frequency of such variants in the UK Biobank population was 1 in 450. The WMH volume was brought forward by ∼11 years in carriers of a rare protease domain variant. A comparison with the effect size of established risk factors for WMH burden revealed that the presence of a rare variant in the HTRA1 protease domain corresponded to a larger effect than meeting the criteria for hypertension (β = 0.26, SE = 0.02, P = 2.9 × 10-59) or being in the upper 99.8% percentile of the distribution of a polygenic risk score based on common genetic variants (β = 0.44, SE = 0.14, P = 0.002). In biochemical experiments, most (6/9) of the identified protease domain variants resulted in markedly reduced protease activity. We further found EGFL8, which showed suggestive evidence for association with WMH volume (P = 1.5 × 10-4, false discovery rate = 0.22) in gene burden tests, to be a direct substrate of HTRA1 and to be preferentially expressed in cerebral arterioles and arteries. In a phenome-wide association study mapping ICD-10 diagnoses to 741 standardized Phecodes, rare variants in the HTRA1 protease domain were associated with multiple neurological and non-neurological conditions including migraine with aura (odds ratio = 12.24, 95%CI: 2.54-35.25; P = 8.3 × 10-5]. Collectively, these findings highlight an important role of rare genetic variation and the HTRA1 protease in determining WMH burden in the general population.

Assessing the role of rare genetic variants in drug-resistant, non-lesional focal epilepsy.

ObjectiveResistance to antiseizure medications (ASMs) is one of the major concerns in the treatment of epilepsy. Despite the increasing number of ASMs available, the proportion of individuals with drug‐resistant epilepsy remains unchanged. In this study, we aimed to investigate the role of rare genetic variants in ASM resistance.MethodsWe performed exome sequencing of 1,128 individuals with non‐familial non‐acquired focal epilepsy (NAFE) (762 non‐responders, 366 responders) and were provided with 1,734 healthy controls. We undertook replication in a cohort of 350 individuals with NAFE (165 non‐responders, 185 responders). We performed gene‐based and gene‐set‐based kernel association tests to investigate potential enrichment of rare variants in relation to drug response status and to risk for NAFE.ResultsWe found no gene or gene set that reached genome‐wide significance. Yet, we identified several prospective candidate genes – among them DEPDC5, which showed a potential association with resistance to ASMs. We found some evidence for an enrichment of truncating variants in dominant familial NAFE genes in our cohort of non‐familial NAFE and in association with drug‐resistant NAFE.InterpretationOur study identifies potential candidate genes for ASM resistance. Our results corroborate the role of rare variants for non‐familial NAFE and imply their involvement in drug‐resistant epilepsy. Future large‐scale genetic research studies are needed to substantiate these findings.

Rare Pathogenic Variants in Mitochondrial and Inflammation-Associated Genes May Lead to Inflammatory Cardiomyopathy in Chagas Disease

Cardiomyopathies are an important cause of heart failure and sudden cardiac death. Little is known about the role of rare genetic variants in inflammatory cardiomyopathy. Chronic Chagas disease cardiomyopathy (CCC) is an inflammatory cardiomyopathy prevalent in Latin America, developing in 30% of the 6 million patients chronically infected by the protozoan Trypanosoma cruzi, while 60% remain free of heart disease (asymptomatic (ASY)). The cytokine interferon-γ and mitochondrial dysfunction are known to play a major pathogenetic role. Chagas disease provides a unique model to probe for genetic variants involved in inflammatory cardiomyopathy.MethodsWe used whole exome sequencing to study nuclear families containing multiple cases of Chagas disease. We searched for rare pathogenic variants shared by all family members with CCC but absent in infected ASY siblings and in unrelated ASY.ResultsWe identified heterozygous, pathogenic variants linked to CCC in all tested families on 22 distinct genes, from which 20 were mitochondrial or inflammation-related – most of the latter involved in proinflammatory cytokine production. Significantly, incubation with IFN-γ on a human cardiomyocyte line treated with an inhibitor of dihydroorotate dehydrogenase brequinar (enzyme showing a loss-of-function variant in one family) markedly reduced mitochondrial membrane potential (ΔψM), indicating mitochondrial dysfunction.ConclusionMitochondrial dysfunction and inflammation may be genetically determined in CCC, driven by rare genetic variants. We hypothesize that CCC-linked genetic variants increase mitochondrial susceptibility to IFN-γ-induced damage in the myocardium, leading to the cardiomyopathy phenotype in Chagas disease. This mechanism may also be operative in other inflammatory cardiomyopathies.

Assessing the Role of Rare Genetic Variation in Patients With Heart Failure

Sequencing studies have identified causal genetic variants for distinct subtypes of heart failure (HF) such as hypertrophic or dilated cardiomyopathy. However, the role of rare, high-impact variants in HF, for which ischemic heart disease is the leading cause, has not been systematically investigated. To assess the contribution of rare variants to all-cause HF with and without reduced left ventricular ejection fraction. This was a retrospective analysis of clinical trials and a prospective epidemiological resource (UK Biobank). Whole-exome sequencing of patients with HF was conducted from the Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity (CHARM) and Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) clinical trials. Data were collected from March 1999 to May 2003 for the CHARM studies and September 2003 to July 2007 for the CORONA study. Using a gene-based collapsing approach, the proportion of patients with HF and controls carrying rare and presumed deleterious variants was compared. The burden of pathogenic variants in known cardiomyopathy genes was also investigated to assess the diagnostic yield. Exome sequencing data were generated between January 2018 and October 2018, and analysis began October 2018 and ended April 2020. Odds ratios and P values for genes enriched for rare and presumed deleterious variants in either patients with HF or controls and diagnostic yield of pathogenic variants in known cardiomyopathy genes. This study included 5942 patients with HF and 13 156 controls. The mean (SD) age was 68.9 (9.9) years and 4213 (70.9%) were male. A significant enrichment of protein-truncating variants in the TTN gene (P = 3.35 × 10-13; odds ratio, 2.54; 95% CI, 1.96-3.31) that was further increased after restriction to variants in exons constitutively expressed in the heart (odds ratio, 4.52; 95% CI, 3.10-6.68). Validation using UK Biobank data showed a similar enrichment (odds ratio, 4.97; 95% CI, 3.94-6.19 after restriction). In the clinical trials, 201 of 5916 patients with HF (3.4%) had a pathogenic or likely pathogenic cardiomyopathy variant implicating 21 different genes. Notably, 121 of 201 individuals (60.2%) had ischemic heart disease as the clinically identified etiology for the HF. Individuals with HF and preserved ejection fraction had only a slightly lower yield than individuals with midrange or reduced ejection fraction (20 of 767 [2.6%] vs 15 of 392 [3.8%] vs 166 of 4757 [3.5%]). An increased burden of diagnostic mendelian cardiomyopathy variants in a broad group of patients with HF of mostly ischemic etiology compared with controls was observed. This work provides further evidence that mendelian genetic conditions may represent an important subset of complex late-onset diseases such as HF, irrespective of the clinical presentation.

P18 Investigating the role of rare genetic variants and susceptibility to juvenile idiopathic arthritis highlights the importance of monogenic disease genes

Abstract Background Juvenile idiopathic arthritis (JIA) is a rheumatic disease, onset before the age of sixteen. JIA is a common complex disease, with contributions from both genetic and environmental risk factors. However, given the young age of onset for JIA, it is possible that genetic risk factors influence susceptibility to a greater extent than environmental risk factors. While several susceptibility loci have been identified for JIA, they are mainly genetic variants that are common in the population. The role of rare genetic variants has not yet been fully explored in JIA. Therefore, the aims of this research were to use rare (&amp;lt;5%MAF) variant based analysis to further define the genetic architecture of JIA. Methods A total of 2,162 UK JIA cases were genotyped using the Illumina HumanCoreExome array and the Understanding Society’s UK household longitudinal study provided the genotype data for 9196 controls. Single variant analysis was used to calculate the association of variants to JIA susceptibility. Gene-based aggregation analysis, specifically the SKAT-O method, were used to calculate the association of whole gene regions to JIA cases. This gene-based aggregation method increases the statistical power of associations, which is valuable when attempting to identify rare variants. Study-wide significance for this research was calculated using a Bonferroni corrected threshold (P = 3.34x10-6). Results Several strongly associated candidate gene regions were identified using SKAT-O analysis. Firstly, the region mevalonate kinase (MVK) (P = 3.95x10-10) was found to be strongly associated. MVK has been reported in mevalonate kinase deficiency, a rare juvenile disease with a phenotype akin to systemic JIA. PYCR1 (P = 1.97x10-9) was an additional region of interest. Variants in this region have been reported in geroderma osteodysplasticum; a disease that results in dysplasia of the hips, hyperextensible joints and skeletal changes. The region WISP3 (P = 8.52x10-9) was also strongly associated. Variants from this region have previously been reported in progressive pseudorheumatoid dysplasia; a disease that can be clinically misdiagnosed with JIA due to similarities in phenotypes. Furthermore, LILRA2 (P = 2.89x10-7) presented as a strong candidate region, with the gene being upregulated in synovial tissue of rheumatoid arthritis patients. Conclusion This analysis has identified promising candidate genes that influence susceptibility to JIA and highlights two key points. Firstly, gene-burden tests of rare variants have the potential to identify novel susceptibility genes for juvenile-onset disease. While MVK and WISP3 have previously been reported to be associated with JIA, these associations were modest, and the current study provides compelling evidence to support their importance. Secondly, the results highlight the importance of investigating the contribution of monogenic genes in juvenile-onset common complex disease. Disclosures M.K. Tordoff None. T.A. Briggs None. S.L. Smith None. A. Yarwood None. W. Thomson None. J. Bowes None.

Testing association of rare genetic variants with resistance to three common antiseizure medications.

Drug resistance is a major concern in the treatment of individuals with epilepsy. No genetic markers for resistance to individual antiseizure medication (ASM) have yet been identified. We aimed to identify the role of rare genetic variants in drug resistance for three common ASMs: levetiracetam (LEV), lamotrigine (LTG), and valproic acid (VPA). A cohort of 1622 individuals of European descent with epilepsy was deeply phenotyped and underwent whole exome sequencing (WES), comprising 575 taking LEV, 826 LTG, and 782 VPA. We performed gene- and gene set-based collapsing analyses comparing responders and nonresponders to the three drugs to determine the burden of different categories of rare genetic variants. We observed a marginally significant enrichment of rare missense, truncating, and splice region variants in individuals who were resistant to VPA compared to VPA responders for genes involved in VPA pharmacokinetics. We also found a borderline significant enrichment of truncating and splice region variants in the synaptic vesicle glycoprotein (SV2) gene family in nonresponders compared to responders to LEV. We did not see any significant enrichment using a gene-based approach. In our pharmacogenetic study, we identified a slightly increased burden of damaging variants in gene groups related to drug kinetics or targeting in individuals presenting with drug resistance to VPA or LEV. Such variants could thus determine a genetic contribution to drug resistance.

Multiple Sclerosis patients carry an increased burden of exceedingly rare genetic variants in the inflammasome regulatory genes

The role of rare genetic variation and the innate immune system in the etiology of multiple sclerosis (MS) is being increasingly recognized. Recently, we described several rare variants in the NLRP1 gene, presumably conveying an increased risk for familial MS. In the present study we aimed to assess rare genetic variation in the inflammasome regulatory network. We performed whole exome sequencing of 319 probands, comprising patients with familial MS, sporadic MS and control subjects. 62 genes involved in the NLRP1/NLRP3 inflammasome regulation were screened for potentially pathogenic rare genetic variation. Aggregate mutational burden was analyzed, considering the variants’ predicted pathogenicity and frequency in the general population. We demonstrate an increased (p = 0.00004) variant burden among MS patients which was most pronounced for the exceedingly rare variants with high predicted pathogenicity. These variants were found in inflammasome genes (NLRP1/3, CASP1), genes mediating inflammasome inactivation via auto and mitophagy (RIPK2, MEFV), and genes involved in response to infection with DNA viruses (POLR3A, DHX58, IFIH1) and to type-1 interferons (TYK2, PTPRC). In conclusion, we present new evidence supporting the importance of rare genetic variation in the inflammasome signaling pathway and its regulation via autophagy and interferon-β to the etiology of MS.

Asthma severity, nature or nurture: genetic determinants.

This article reviews the progress in the search for the genetic determinants of severe asthma. Twin studies estimate that approximately 25% of the phenotypic variability in asthma severity is determined by genetic factors, with the remainder determined by nongenetic factors including environmental and psychosocial factors, behavioral traits, and comorbidities. Most genetic association studies of asthma severity performed to date are underpowered and not designed to clearly distinguish asthma severity variants from asthma susceptibility variants. However, the most recent genome-wide asthma severity association study, conducted in more than 57 000 individuals, demonstrated significant associations for 25 loci, including three not previously associated with asthma: GATA3, MUC5AC, and KIAA1109. Of these, the MUC5AC association was restricted to cohorts that included moderate-to-severe (but not mild) asthma. Additional insights from rare monogenic disorders that can present as severe asthma include recognition that loss-of-function variants in the filaggrin gene known to cause ichthyosis vulgaris are consistently associated with more severe asthma outcomes. Other notable loci of interest include RAD50-IL13 on chromosome 5q and the ORMDL3-GSDMB locus on chromosome 17q21. Severe asthma is a polygenic trait. Future research should explore the role of rare genetic variation and gene-by-environment interaction.

SU25 - TARGETED NEXT GENERATION SEQUENCING OF 187 GENES IN A BULGARIAN PSYCHOSIS SAMPLE

Background There is strong evidence for partial overlap of genetic influence on Schizophrenia (SCZ), Schizoaffective Disorder (SAD) and Bipolar Affective Disorder (BAD). Part of this is due to common genetic variants, detected by GWAS, with a small individual effect on risk. Recent studies using next generation sequencing reveal growing evidence of the role of rare genetic variants in both diseases. We performed targeted NGS on 187 candidate genes to further investigate the genetic architecture of Bulgarian patients with bipolar disorder and schizophrenia. Methods A total of 300 individuals with BAD, 151 with SCZ, 15 SAD according to DSMIV and ICD-10, as well as 85 healthy population controls and 40 healthy relatives were recruited. The samples were sequenced on the Ion PROTON platform. The sequencing panel comprised of 187 preselected strong candidate genes, based on the results from GWAS and previous NGS studies. Only samples with coverage of at least 95% of the target region at 20x were included in the analyses. Case-control association testing was done using PLINK. The rare variants have been evaluated and divided into groups based on their functional relevance: LOF variants (frameshift and nonsense); with potentially damaging effect on protein function (splice site, missense variants, 3’-UTR/5’-UTR variants); and with no known effect on function (synonymous and intron variants). Genes were prioritized by mutation burden analysis based on the average number of functional occurrences per 1000 bp of the gene CDS. The RVIS scoring system for assessing the intolerance of individual genes to protein-altering variants (Petrovski et al., 2013) was used in conjunction with the burden score for the final ordering. Results 5373 variants were detected, of which 2826 were found in affecteds (1831 singletons and 995 recurrent). No significant associations between cases and controls could be detected, that survived the correction for multiple testing. In total we found in patients 14 rare LOF variants; 889 non-synonymous variants (243 of which were potentially damaging); 109 splice site variants and 32 in regulatory regions. Discussion We could find no significant association of common or rare variants in the analyzed samples, most likely due to small sample size. However, we could identify both recurrent and singleton rare variants with potential functional relevance in genes associated with ion channels, postsynaptic plasticity, neurogenesis and signalling cascade pathways.

Rare variants and de novo variants in mesial temporal lobe epilepsy with hippocampal sclerosis.

ObjectiveWe investigated the role of rare genetic variants and of de novo variants in the pathogenesis of mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE-HS).MethodsWhole-exome sequencing (WES) was performed in patients with MTLE-HS and their unaffected parents (trios). Genes or gene sets that were enriched with predicted damaging rare variants in the patients as compared to population controls were identified. Patients and their parents were compared to identify whether the variants were de novo or inherited.ResultsAfter quality control, WES data from 47 patients (26 female), including 23 complete trios, were available for analysis. Compared with population controls, significant enrichment of rare variants was observed in SEC24B. Integration of gene set data describing neuronal functions and psychiatric disorders showed enrichment signal on fragile X mental retardation protein (FMRP) targets. Twenty-one de novo variants were identified, with many known to cause neuropsychiatric disorders. The FMRP-targeted genes also carried more de novo variants. Inherited compound heterozygous and homozygous variants were identified.ConclusionsThe genetic architecture underlying MTHE-HS is complex. Multiple genes carrying de novo variants and rare variants among FMRP targets were identified, suggesting a pathogenic role. MTLE-HS and other neuropsychiatric disorders may have shared biology.

A genome-wide association study of red-blood cell fatty acids and ratios incorporating dietary covariates: Framingham Heart Study Offspring Cohort.

Recent analyses have suggested a strong heritable component to circulating fatty acid (FA) levels; however, only a limited number of genes have been identified which associate with FA levels. In order to expand upon a previous genome wide association study done on participants in the Framingham Heart Study Offspring Cohort and FA levels, we used data from 2,400 of these individuals for whom red blood cell FA profiles, dietary information and genotypes are available, and then conducted a genome-wide evaluation of potential genetic variants associated with 22 FAs and 15 FA ratios, after adjusting for relevant dietary covariates. Our analysis found nine previously identified loci associated with FA levels (FADS, ELOVL2, PCOLCE2, LPCAT3, AGPAT4, NTAN1/PDXDC1, PKD2L1, HBS1L/MYB and RAB3GAP1/MCM6), while identifying four novel loci. The latter include an association between variants in CALN1 (Chromosome 7) and eicosapentaenoic acid (EPA), DHRS4L2 (Chromosome 14) and a FA ratio measuring delta-9-desaturase activity, as well as two loci associated with less well understood proteins. Thus, the inclusion of dietary covariates had a modest impact, helping to uncover four additional loci. While genome-wide association studies continue to uncover additional genes associated with circulating FA levels, much of the heritable risk is yet to be explained, suggesting the potential role of rare genetic variation, epistasis and gene-environment interactions on FA levels as well. Further studies are needed to continue to understand the complex genetic picture of FA metabolism and synthesis.

An Exome Sequencing Study to Assess the Role of Rare Genetic Variation in Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is an increasingly recognized, often fatal lung disease of unknown etiology. The aim of this study was to use whole-exome sequencing to improve understanding of the genetic architecture of pulmonary fibrosis. We performed a case-control exome-wide collapsing analysis including 262 unrelated individuals with pulmonary fibrosis clinically classified as IPF according to American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guidelines (81.3%), usual interstitial pneumonia secondary to autoimmune conditions (11.5%), or fibrosing nonspecific interstitial pneumonia (7.2%). The majority (87%) of case subjects reported no family history of pulmonary fibrosis. We searched 18,668 protein-coding genes for an excess of rare deleterious genetic variation using whole-exome sequence data from 262 case subjects with pulmonary fibrosis and 4,141 control subjects drawn from among a set of individuals of European ancestry. Comparing genetic variation across 18,668 protein-coding genes, we found a study-wide significant (P < 4.5 × 10-7) case enrichment of qualifying variants in TERT, RTEL1, and PARN. A model qualifying ultrarare, deleterious, nonsynonymous variants implicated TERT and RTEL1, and a model specifically qualifying loss-of-function variants implicated RTEL1 and PARN. A subanalysis of 186 case subjects with sporadic IPF confirmed TERT, RTEL1, and PARN as study-wide significant contributors to sporadic IPF. Collectively, 11.3% of case subjects with sporadic IPF carried a qualifying variant in one of these three genes compared with the 0.3% carrier rate observed among control subjects (odds ratio, 47.7; 95% confidence interval, 21.5-111.6; P = 5.5 × 10-22). We identified TERT, RTEL1, and PARN-three telomere-related genes previously implicated in familial pulmonary fibrosis-as significant contributors to sporadic IPF. These results support the idea that telomere dysfunction is involved in IPF pathogenesis.

Parsing psychosis subtypes through investigations of rare genetic variants

Parsing psychosis subtypes through investigations of rare genetic variants

Explaining the variable penetrance of CNVs: Parental intelligence modulates expression of intellectual impairment caused by the 22q11.2 deletion.

The role of rare genetic variants, in particular copy number variants (CNVs), in the etiology of neurodevelopmental disorders is becoming increasingly clear. While the list of these disorder-related CNVs continues to lengthen, it has also become clear that in nearly all genetic variants the proportion of carriers who express the associated phenotype is far from 100%. To understand this variable penetrance of CNVs it is important to realize that even the largest CNVs represent only a tiny fraction of the entire genome. Therefore, part of the mechanism underlying the variable penetrance of CNVs is likely the modulatory impact of the rest of the genome. In the present study we used the 22q11DS as a model to examine whether the observed penetrance of intellectual impairment-one of the main phenotypes associated with 22q11DS-is modulated by the intellectual level of their parents, for which we used the parents' highest level of education as a proxy. Our results, based on data observed in 171 children with 22q11DS in the age range of 5-15 years, showed a significant association between estimated parental cognitive level and intelligence in offspring (full scale, verbal and performance IQ), with the largest effect size for verbal IQ. These results suggest that possible mechanisms involved in the variable penetrance observed in CNVs include the impact of genetic background and/or environmental influences. © 2016 Wiley Periodicals, Inc.

Dissecting the genetic determinants of hemostasis and thrombosis.

New DNA genotyping and sequencing technologies have facilitated the rapid advancement in our knowledge of human genomic variation and a search for the heritable determinants of complex genetic traits. This review highlights findings from recent genetic studies of complex traits primarily related to venous thromboembolism and provides tools to understand and interpret genome-wide association studies and next-generation sequencing studies. Genome-wide studies of venous thromboembolic disease and the variation of the protein components of the hemostatic system have been reported. The results of these studies have suggested that variants in a diverse set of known and new genes contribute to the heritability of these traits, but that many of the genetic determinants of these traits still remain undiscovered. Next-generation sequencing studies and functional studies of the gene loci that contribute to hemostatic traits are currently underway. Future studies that explore the role of rare genetic variants, regulatory elements of the genome and gene-gene interactions will be required for a more complete understanding of the genetic control of the hemostatic system and for the application of this knowledge to the care of patients with disorders of thrombosis and hemostasis.