scholarly journals Exome Sequencing to Detect Rare Variants Associated With General Cognitive Ability: A Pilot Study

2015 ◽  
Vol 18 (2) ◽  
pp. 117-125 ◽  
Author(s):  
Michelle Luciano ◽  
Victoria Svinti ◽  
Archie Campbell ◽  
Riccardo E. Marioni ◽  
Caroline Hayward ◽  
...  
Keyword(s):  
Cognitive Ability ◽  
Exome Sequencing ◽  
Genetic Variants ◽  
Complex Traits ◽  
Rare Variants ◽  
Copy Number Variant ◽  
Apical Part ◽  
General Cognitive Ability ◽  
Sequencing Studies ◽  
Rare Genetic Variants

Variation in human cognitive ability is of consequence to a large number of health and social outcomes and is substantially heritable. Genetic linkage, genome-wide association, and copy number variant studies have investigated the contribution of genetic variation to individual differences in normal cognitive ability, but little research has considered the role of rare genetic variants. Exome sequencing studies have already met with success in discovering novel trait-gene associations for other complex traits. Here, we use exome sequencing to investigate the effects of rare variants on general cognitive ability. Unrelated Scottish individuals were selected for high scores on a general component of intelligence (g). The frequency of rare genetic variants (in n = 146) was compared with those from Scottish controls (total n = 486) who scored in the lower to middle range of the g distribution or on a proxy measure of g. Biological pathway analysis highlighted enrichment of the mitochondrial inner membrane component and apical part of cell gene ontology terms. Global burden analysis showed a greater total number of rare variants carried by high g cases versus controls, which is inconsistent with a mutation load hypothesis whereby mutations negatively affect g. The general finding of greater non-synonymous (vs. synonymous) variant effects is in line with evolutionary hypotheses for g. Given that this first sequencing study of high g was small, promising results were found, suggesting that the study of rare variants in larger samples would be worthwhile.

scholarly journals Putative second hit rare genetic variants in families with seemingly GBA-associated Parkinson’s disease

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Muhammad Aslam ◽  
Nirosiya Kandasamy ◽  
Anwar Ullah ◽  
Nagarajan Paramasivam ◽  
Mehmet Ali Öztürk ◽  
...  
Keyword(s):  
Risk Factors ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Variants ◽  
Rare Variants ◽  
Alpha Synuclein ◽  
Younger Age ◽  
Targeted Treatments ◽  
Genes Encoding ◽  
Rare Genetic Variants

AbstractRare variants in the beta-glucocerebrosidase gene (GBA1) are common genetic risk factors for alpha synucleinopathy, which often manifests clinically as GBA-associated Parkinson’s disease (GBA-PD). Clinically, GBA-PD closely mimics idiopathic PD, but it may present at a younger age and often aggregates in families. Most carriers of GBA variants are, however, asymptomatic. Moreover, symptomatic PD patients without GBA variant have been reported in families with seemingly GBA-PD. These observations obscure the link between GBA variants and PD pathogenesis and point towards a role for unidentified additional genetic and/or environmental risk factors or second hits in GBA-PD. In this study, we explored whether rare genetic variants may be additional risk factors for PD in two families segregating the PD-associated GBA1 variants c.115+1G>A (ClinVar ID: 93445) and p.L444P (ClinVar ID: 4288). Our analysis identified rare genetic variants of the HSP70 co-chaperone DnaJ homolog subfamily B member 6 (DNAJB6) and lysosomal protein prosaposin (PSAP) as additional factors possibly influencing PD risk in the two families. In comparison to the wild-type proteins, variant DNAJB6 and PSAP proteins show altered functions in the context of cellular alpha-synuclein homeostasis when expressed in reporter cells. Furthermore, the segregation pattern of the rare variants in the genes encoding DNAJB6 and PSAP indicated a possible association with PD in the respective families. The occurrence of second hits or additional PD cosegregating rare variants has important implications for genetic counseling in PD families with GBA1 variant carriers and for the selection of PD patients for GBA targeted treatments.

scholarly journals Identification of rare genetic variants in Juvenile Idiopathic Arthritis using whole exome sequencing

2015 ◽  
Vol 13 (S1) ◽  
Author(s):  
E Sanchez ◽  
S Grandemange ◽  
F Tran Mau-Them ◽  
P Louis-Plence ◽  
A Carbasse ◽  
...  
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Variants ◽  
Whole Exome ◽  
Rare Genetic Variants

Whole‐Exome Sequencing of a Saudi Epilepsy Cohort Reveals Association Signals in Known and Potentially Novel Loci

2021 ◽  
Author(s):  
Amein Kadhem AlAli ◽  
Abdulrahman Al-Enazi ◽  
Ahmed Ammar ◽  
Mahmoud Hajj ◽  
Cyril Cyrus ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Rare Variants ◽  
High Rate ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Novel Variants ◽  
Unknown Significance ◽  
Rare Genetic Variants

Abstract Background Epilepsy, a serious chronic neurological condition effecting up to 100 million people globally, has clear genetic underpinnings including common and rare variants. In Saudi Arabia the prevalence of epilepsy is high and caused mainly by perinatal and genetic factors. No whole-exome sequencing (WES) studies have been performed to date in Saudi Arabian Epilepsy cohorts. This offers a unique opportunity for the discovery of rare genetic variants impacting this disease as there is a high rate of consanguinity amongst large tribal pedigrees. Results We performed WES on 144 individuals diagnosed with epilepsy, to interrogate known Epilepsy related genes for known and functional novel variants. We also used an American College of Medical Genetics (ACMG) guideline based variant prioritization approach in an attempt to discover putative causative variants. We identified a 32 potentially causative pathogenic variants across 30 different genes in 44/144 (30%) of these Saudi Epilepsy individuals. We also identified 232 variants of unknown significance (VUS) across 101 different genes in 133/144 (92%) subjects. Strong enrichment of variants of likely pathogenicity were observed in previously described epilepsy-associated loci, and a number of putative pathogenic variants in novel loci are also observed. Conclusion Several putative pathogenic variants known to be epilepsy-related loci were identified for the first time in our population, in addition to several potential new loci have been identified which may be prioritized for further investigation.

scholarly journals The total burden of rare, non-synonymous exome genetic variants is not associated with childhood or late-life cognitive ability

2014 ◽  
Vol 281 (1781) ◽  
pp. 20140117 ◽  
Author(s):  
Riccardo E. Marioni ◽  
Lars Penke ◽  
Gail Davies ◽  
Jennifer E. Huffman ◽  
Caroline Hayward ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Cognitive Ability ◽  
Multiple Testing ◽  
Rare Variants ◽  
A Priori ◽  
Late Life ◽  
General Cognitive Ability ◽  
Birth Cohorts ◽  
Total Burden ◽  
Gain Loss

Human cognitive ability shows consistent, positive associations with fitness components across the life-course. Underlying genetic variation should therefore be depleted by selection, which is not observed. Genetic variation in general cognitive ability (intelligence) could be maintained by a mutation–selection balance, with rare variants contributing to its genetic architecture. This study examines the association between the total number of rare stop-gain/loss, splice and missense exonic variants and cognitive ability in childhood and old age in the same individuals. Exome array data were obtained in the Lothian Birth Cohorts of 1921 and 1936 (combined N = 1596). General cognitive ability was assessed at age 11 years and in late life (79 and 70 years, respectively) and was modelled against the total number of stop-gain/loss, splice, and missense exonic variants, with minor allele frequency less than or equal to 0.01, using linear regression adjusted for age and sex. In both cohorts and in both the childhood and late-life models, there were no significant associations between rare variant burden in the exome and cognitive ability that survived correction for multiple testing. Contrary to our a priori hypothesis, we observed no evidence for an association between the total number of rare exonic variants and either childhood cognitive ability or late-life cognitive ability.

scholarly journals Exome sequencing identifies novel AD-associated genes.

2020 ◽  
Author(s):  
Henne Holstege ◽  
Marc Hulsman ◽  
Camille Charbonnier ◽  
Benjamin Grenier-Boley ◽  
Olivier Quenez ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Genetic Variants ◽  
Rare Variants ◽  
Mendelian Inheritance ◽  
Loss Of Function ◽  
App Processing ◽  
Complex Disorders ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
The Impact

Background: With the development of next-generation sequencing technologies, it is possible to identify rare genetic variants that influence the risk of complex disorders. To date, whole exome sequencing (WES) strategies have shown that specific clusters of damaging rare variants in the TREM2, SORL1 and ABCA7 genes are associated with an increased risk of developing Alzheimers Disease (AD), reaching odds ratios comparable with the APOE-ε4 allele, the main common AD genetic risk factor. Here, we set out to identify additional AD-associated genes by an exome-wide investigation of the burden of rare damaging variants in the genomes of AD cases and cognitively healthy controls. Method: We integrated the data from 25,982 samples from the European ADES consortium and the American ADSP consortium. We developed new techniques to homogenise and analyse these data. Carriers of pathogenic variants in genes associated with Mendelian inheritance of dementia were excluded. After quality control, we used 12,652 AD cases and 8,693 controls for analysis. Genes were analysed using a burden analysis, including both non-synonymous and loss-of-function rare variants, the impact of which was prioritised using REVEL. Result: We confirmed that carrying rare protein-damaging genetic variants in TREM2, SORL1 or ABCA7 is associated with increased AD-risk. Moreover, we found that carrying rare damaging variants in the microglial ATP8B4 gene was significantly associated with AD, and we found suggestive evidence that rare variants in ADAM10, ABCA1, ORC6, B3GNT4 and SRC genes associated with increased AD risk. High-impact variants in these genes were mostly extremely rare and enriched in AD patients with earlier ages at onset. Additionally, we identified two suggestive protective associations in CBX3 and PRSS3. We are currently replicating these associations in independent datasets. Conclusion: With our newly developed homogenisation methods, we identified novel genetic determinants of AD which provide further evidence for a pivotal role of APP processing, lipid metabolism, and microglia and neuro-inflammatory processes in AD pathophysiology.

scholarly journals RAREsim: A simulation method for very rare genetic variants

2021 ◽  
Author(s):  
Megan Null ◽  
Josée Dupuis ◽  
Christopher R. Gignoux ◽  
Audrey E. Hendricks
Keyword(s):  
Rare Variant ◽  
Complex Traits ◽  
Rare Variants ◽  
Simulated Data ◽  
Real Data ◽  
Simulation Method ◽  
Sequencing Data ◽  
Variant Annotation ◽  
Causal Variants ◽  
Rare Genetic Variants

AbstractIdentification of rare variant associations is crucial to fully characterize the genetic architecture of complex traits and diseases. Essential in this process is the evaluation of novel methods in simulated data that mirrors the distribution of rare variants and haplotype structure in real data. Additionally, importing real variant annotation enables in silico comparison of methods that focus on putative causal variants, such as rare variant association tests, and polygenic scoring methods. Existing simulation methods are either unable to employ real variant annotation or severely under- or over-estimate the number of singletons and doubletons reducing the ability to generalize simulation results to real studies. We present RAREsim, a flexible and accurate rare variant simulation algorithm. Using parameters and haplotypes derived from real sequencing data, RAREsim efficiently simulates the expected variant distribution and enables real variant annotations. We highlight RAREsim’s utility across various genetic regions, sample sizes, ancestries, and variant classes.

scholarly journals Detection of rare disease variants in extended pedigrees using RVS

2018 ◽  
Vol 35 (14) ◽  
pp. 2509-2511 ◽  
Author(s):  
Thomas Sherman ◽  
Jack Fu ◽  
Robert B Scharpf ◽  
Alexandre Bureau ◽  
Ingo Ruczinski
Keyword(s):  
Open Source Software ◽  
Genetic Variants ◽  
Supplementary Information ◽  
Case Control Studies ◽  
Extended Pedigrees ◽  
Disease Phenotypes ◽  
Identical By Descent ◽  
Sequencing Studies ◽  
Rare Genetic Variants ◽  
Family Based

Abstract Summary Family-based sequencing studies enable researchers to identify highly penetrant genetic variants too rare to be tested in conventional case-control studies, by studying co-segregation of variant and disease phenotypes. When multiple affected subjects in a family are sequenced, the probability that a variant or a set of variants is shared identical-by-descent by some or all affected relatives provides evidence against the null hypothesis of complete absence of linkage and association. The Rare Variant Sharing software package RVS implements a suite of tools to assess association and linkage between rare genetic variants and a dichotomous disease indicator in family pedigrees. Availability and Implementation RVS is available as open source software from the Bioconductor webpage at https://bioconductor.org/packages/release/bioc/html/RVS.html. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Exome sequencing identifies high-impact trait-associated alleles enriched in Finns

2018 ◽  
Author(s):  
Adam E Locke ◽  
Karyn Meltz Steinberg ◽  
Charleston WK Chiang ◽  
Susan K Service ◽  
Aki S Havulinna ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Quantitative Traits ◽  
Rare Variants ◽  
Mendelian Disease ◽  
Finnish Population ◽  
Isolated Populations ◽  
Deleterious Alleles ◽  
Disease Mutations ◽  
Sequencing Studies ◽  
Novel Associations

ABSTRACTAs yet undiscovered rare variants are hypothesized to substantially influence an individual’s risk for common diseases and traits, but sequencing studies aiming to identify such variants have generally been underpowered. In isolated populations that have expanded rapidly after a population bottleneck, deleterious alleles that passed through the bottleneck may be maintained at much higher frequencies than in other populations. In an exome sequencing study of nearly 20,000 cohort participants from northern and eastern Finnish populations that exemplify this phenomenon, most novel trait-associated deleterious variants are seen only in Finland or display frequencies more than 20 times higher than in other European populations. These enriched alleles underlie 34 novel associations with 21 disease-related quantitative traits and demonstrate a geographical clustering equivalent to that of Mendelian disease mutations characteristic of the Finnish population. Sequencing studies in populations without this unique history would require hundreds of thousands to millions of participants for comparable power for these variants.

scholarly journals Rare variants association testing for a binary outcome when pooling individual level data from heterogeneous studies

2020 ◽  
Author(s):  
Tamar Sofer ◽  
Na Guo
Keyword(s):  
Genetic Variants ◽  
Error Control ◽  
Rare Variants ◽  
Score Test ◽  
Saddlepoint Approximation ◽  
Rare Allele ◽  
Association Testing ◽  
Type 1 Error ◽  
Rare Genetic Variants

AbstractWhole genome and exome sequencing studies are used to test the association of rare genetic variants with health traits. Many existing WGS efforts now aggregate data from heterogeneous groups, e.g. combining sets of individuals of European and African ancestries. We here investigate the statistical implications on rare variant association testing with a binary trait when combining together heterogeneous studies, defined as studies with potentially different disease proportion and different frequency of variant carriers. We study and compare in simulations the type 1 error control and power of the naïve Score test, the saddlepoint approximation to the score test (SPA test), and the BinomiRare test in a range of settings, focusing on low numbers of variant carriers. We show that type 1 error control and power patterns depend on both the number of carriers of the rare allele and on disease prevalence in each of the studies. We develop recommendations for association analysis of rare genetic variants. (1) The Score test is preferred when the case proportion in the sample is 50%. (2) Do not down-sample controls to balance case-control ratio, because it reduces power. Rather, use a test that controls the type 1 error. (3) Conduct stratified analysis in parallel with combined analysis. Aggregated testing may have lower power when the variant effect size differs between strata.

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