scholarly journals Testing rare variants for hypertension using family-based tests with different weighting schemes

2016 ◽  
Vol 10 (S7) ◽  
Author(s):  
Xuexia Wang ◽  
Xingwang Zhao ◽  
Jin Zhou
Keyword(s):  
Rare Variants ◽  
Weighting Schemes ◽  
Family Based

scholarly journals Identification of sixteen novel candidate genes for late onset Parkinson’s disease

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Alessandro Gialluisi ◽  
Mafalda Giovanna Reccia ◽  
Nicola Modugno ◽  
Teresa Nutile ◽  
Alessia Lombardi ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Candidate Genes ◽  
Rare Variants ◽  
Late Onset ◽  
High Specificity ◽  
Diagnostic Tools ◽  
Multi Stage ◽  
Whole Exome ◽  
Family Based

Abstract Background Parkinson’s disease (PD) is a neurodegenerative movement disorder affecting 1–5% of the general population for which neither effective cure nor early diagnostic tools are available that could tackle the pathology in the early phase. Here we report a multi-stage procedure to identify candidate genes likely involved in the etiopathogenesis of PD. Methods The study includes a discovery stage based on the analysis of whole exome data from 26 dominant late onset PD families, a validation analysis performed on 1542 independent PD patients and 706 controls from different cohorts and the assessment of polygenic variants load in the Italian cohort (394 unrelated patients and 203 controls). Results Family-based approach identified 28 disrupting variants in 26 candidate genes for PD including PARK2, PINK1, DJ-1(PARK7), LRRK2, HTRA2, FBXO7, EIF4G1, DNAJC6, DNAJC13, SNCAIP, AIMP2, CHMP1A, GIPC1, HMOX2, HSPA8, IMMT, KIF21B, KIF24, MAN2C1, RHOT2, SLC25A39, SPTBN1, TMEM175, TOMM22, TVP23A and ZSCAN21. Sixteen of them have not been associated to PD before, were expressed in mesencephalon and were involved in pathways potentially deregulated in PD. Mutation analysis in independent cohorts disclosed a significant excess of highly deleterious variants in cases (p = 0.0001), supporting their role in PD. Moreover, we demonstrated that the co-inheritance of multiple rare variants (≥ 2) in the 26 genes may predict PD occurrence in about 20% of patients, both familial and sporadic cases, with high specificity (> 93%; p = 4.4 × 10− 5). Moreover, our data highlight the fact that the genetic landmarks of late onset PD does not systematically differ between sporadic and familial forms, especially in the case of small nuclear families and underline the importance of rare variants in the genetics of sporadic PD. Furthermore, patients carrying multiple rare variants showed higher risk of manifesting dyskinesia induced by levodopa treatment. Conclusions Besides confirming the extreme genetic heterogeneity of PD, these data provide novel insights into the genetic of the disease and may be relevant for its prediction, diagnosis and treatment.

Abstract 12: Heritability of Ischemic Stroke and its Subtypes

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Andrew E Bluher ◽  
Michael A Nalls ◽  
John W Cole ◽  
Pankaj Sharma ◽  
James F Meschia ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Fixed Effects ◽  
Rare Variants ◽  
Phenotypic Variability ◽  
Fixed Effects Model ◽  
Stroke Subtype ◽  
Genome Wide ◽  
Weighted Means ◽  
Family Based ◽  
And Gender

Background and Purpose: Family-based methods for estimating heritability cannot discriminate between shared genetic and shared environmental exposures. Recently, methods have been developed for estimating heritability in population samples using genome-wide SNPs. We used the approach developed by Visscher and colleagues to estimate the heritability of ischemic stroke in Caucasian subjects. In addition to evaluating the overall heritability of ischemic stroke, we assessed whether stroke heritability varies by age, gender, and stroke subtype. Methods: Using publicly available software (GCTA and PLINK), we estimated ischemic stroke heritability stratified by age and gender using genome-wide association (GWA) data from three Caucasian ischemic stroke studies: Ischemic Stroke Genetics Study (ISGS), Bio-Repository of DNA in Stroke (BRAINS), and Genetics of Early-Onset Stroke (GEOS). Weighted means of site-specific heritability point estimates were combined according to a standard fixed effects model. Results: Conclusions: A SNP-based approach may be useful in discerning differences in ischemic stroke heritability between different cohorts and subtypes. Overall, our analysis estimated ischemic stroke heritability to be 31% (SE = 7%), with a suggestion of higher heritability for younger cases. Small vessel stroke showed the highest heritability (58 ± 19%), with cardioembolic showing the lowest heritability (16 ± 14%). It should be emphasized that heritability estimates are population-specific and that the method used only reflects the heritability captured by common SNP variants measured in GWA studies, and not phenotypic variability explained by rare variants.

scholarly journals Rare variants in Protein tyrosine phosphatase, receptor type A (PTPRA) in schizophrenia: Evidence from a family based study

2019 ◽  
Vol 206 ◽  
pp. 75-81
Author(s):  
Jibin John ◽  
Prachi Kukshal ◽  
Aditya Sharma ◽  
Triptish Bhatia ◽  
V.L. Nimgaonkar ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Rare Variants ◽  
Tyrosine Phosphatase ◽  
Type A ◽  
Receptor Type ◽  
Protein Tyrosine ◽  
Family Based

scholarly journals An exact, unifying framework for region-based association testing in family-based designs, including higher criticism approaches, SKATs, multivariate and burden tests

2019 ◽  
Author(s):  
Julian Hecker ◽  
F. William Townes ◽  
Priyadarshini Kachroo ◽  
Jessica Lasky-Su ◽  
John Ziniti ◽  
...  
Keyword(s):  
Rare Variants ◽  
Genotype Distribution ◽  
Test Statistics ◽  
Test Statistic ◽  
Higher Criticism ◽  
Association Testing ◽  
Simulation Based ◽  
The Family ◽  
Family Based ◽  
Burden Tests

AbstractAnalysis of rare variants in family-based studies remains a challenge. To perform a region/set-based association analysis of rare variants in family-based studies, we propose a general methodological framework that integrates higher criticism, maximum, SKATs, and burden approaches into the family-based association testing (FBAT) framework. Using the haplotype algorithm for FBATs to compute the conditional genotype distribution under the null hypothesis of Mendelian transmissions, virtually any association test statistics can be implemented in our approach and simulation-based or exact p-values can be computed without the need for asymptotic settings. Using simulations, we compare the features of the proposed test statistics in our framework with the existing region-based methodology for family-based studies under various scenarios. The tests of our framework outperform the existing approaches. We provide general guidelines for which scenarios, e.g., sparseness of the signals or local LD structure, which test statistic will have distinct power advantages over the others. We also illustrate our approach in an application to a whole-genome sequencing dataset with 897 asthmatic trios.

scholarly journals Demographic history mediates the effect of stratification on polygenic scores

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Arslan A Zaidi ◽  
Iain Mathieson
Keyword(s):  
Principal Components ◽  
Population Stratification ◽  
Rare Variants ◽  
Association Studies ◽  
Demographic History ◽  
Hybrid Approach ◽  
Genome Wide Association Studies ◽  
Environmental Structure ◽  
Polygenic Scores ◽  
Family Based

Population stratification continues to bias the results of genome-wide association studies (GWAS). When these results are used to construct polygenic scores, even subtle biases can cumulatively lead to large errors. To study the effect of residual stratification, we simulated GWAS under realistic models of demographic history. We show that when population structure is recent, it cannot be corrected using principal components of common variants because they are uninformative about recent history. Consequently, polygenic scores are biased in that they recapitulate environmental structure. Principal components calculated from rare variants or identity-by-descent segments can correct this stratification for some types of environmental effects. While family-based studies are immune to stratification, the hybrid approach of ascertaining variants in GWAS but reestimating effect sizes in siblings reduces but does not eliminate stratification. We show that the effect of population stratification depends not only on allele frequencies and environmental structure but also on demographic history.

scholarly journals Evaluation of the power and type I error of recently proposed family-based tests of association for rare variants

2014 ◽  
Vol 8 (Suppl 1) ◽  
pp. S36 ◽  
Author(s):  
Allison Hainline ◽  
Carolina Alvarez ◽  
Alexander Luedtke ◽  
Brian Greco ◽  
Andrew Beck ◽  
...  
Keyword(s):  
Type I Error ◽  
Rare Variants ◽  
Type I ◽  
Tests Of Association ◽  
Family Based

scholarly journals Deep genotype imputation captures virtually all heritability of autoimmune vitiligo

2020 ◽  
Vol 29 (5) ◽  
pp. 859-863 ◽  
Author(s):  
Genevieve H L Roberts ◽  
Stephanie A Santorico ◽  
Richard A Spritz
Keyword(s):  
Complex Disease ◽  
Rare Variants ◽  
Association Studies ◽  
Genotype Imputation ◽  
Genome Wide Association Studies ◽  
Common Variants ◽  
Genome Wide ◽  
Autoimmune Vitiligo ◽  
Family Based ◽  
Project Data

Abstract Autoimmune vitiligo is a complex disease involving polygenic risk from at least 50 loci previously identified by genome-wide association studies. The objectives of this study were to estimate and compare vitiligo heritability in European-derived patients using both family-based and ‘deep imputation’ genotype-based approaches. We estimated family-based heritability (h2FAM) by vitiligo recurrence among a total 8034 first-degree relatives (3776 siblings, 4258 parents or offspring) of 2122 unrelated vitiligo probands. We estimated genotype-based heritability (h2SNP) by deep imputation to Haplotype Reference Consortium and the 1000 Genomes Project data in unrelated 2812 vitiligo cases and 37 079 controls genotyped genome wide, achieving high-quality imputation from markers with minor allele frequency (MAF) as low as 0.0001. Heritability estimated by both approaches was exceedingly high; h2FAM = 0.75–0.83 and h2SNP = 0.78. These estimates are statistically identical, indicating there is essentially no remaining ‘missing heritability’ for vitiligo. Overall, ~70% of h2SNP is represented by common variants (MAF > 0.01) and 30% by rare variants. These results demonstrate that essentially all vitiligo heritable risk is captured by array-based genotyping and deep imputation. These findings suggest that vitiligo may provide a particularly tractable model for investigation of complex disease genetic architecture and predictive aspects of personalized medicine.

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