Rare Variant Analysis in Unrelated Individuals

Abstract Background Pulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by pathogenic remodeling of pulmonary arterioles leading to increased pulmonary pressures, right ventricular hypertrophy, and heart failure. PAH can be associated with other diseases (APAH: connective tissue diseases, congenital heart disease, and others) but often the etiology is idiopathic (IPAH). Mutations in bone morphogenetic protein receptor 2 (BMPR2) are the cause of most heritable cases but the vast majority of other cases are genetically undefined. Methods To identify new risk genes, we utilized an international consortium of 4241 PAH cases with exome or genome sequencing data from the National Biological Sample and Data Repository for PAH, Columbia University Irving Medical Center, and the UK NIHR BioResource – Rare Diseases Study. The strength of this combined cohort is a doubling of the number of IPAH cases compared to either national cohort alone. We identified protein-coding variants and performed rare variant association analyses in unrelated participants of European ancestry, including 1647 IPAH cases and 18,819 controls. We also analyzed de novo variants in 124 pediatric trios enriched for IPAH and APAH-CHD. Results Seven genes with rare deleterious variants were associated with IPAH with false discovery rate smaller than 0.1: three known genes (BMPR2, GDF2, and TBX4), two recently identified candidate genes (SOX17, KDR), and two new candidate genes (fibulin 2, FBLN2; platelet-derived growth factor D, PDGFD). The new genes were identified based solely on rare deleterious missense variants, a variant type that could not be adequately assessed in either cohort alone. The candidate genes exhibit expression patterns in lung and heart similar to that of known PAH risk genes, and most variants occur in conserved protein domains. For pediatric PAH, predicted deleterious de novo variants exhibited a significant burden compared to the background mutation rate (2.45×, p = 2.5e−5). At least eight novel pediatric candidate genes carrying de novo variants have plausible roles in lung/heart development. Conclusions Rare variant analysis of a large international consortium identified two new candidate genes—FBLN2 and PDGFD. The new genes have known functions in vasculogenesis and remodeling. Trio analysis predicted that ~ 15% of pediatric IPAH may be explained by de novo variants.

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On the substructure controls in rare variant analysis: Principal components or variance components?

Genetic Epidemiology ◽

10.1002/gepi.22102 ◽

2017 ◽

Vol 42 (3) ◽

pp. 276-287 ◽

Cited By ~ 2

Author(s):

Yiwen Luo ◽

Arnab Maity ◽

Michael C. Wu ◽

Chris Smith ◽

Qing Duan ◽

...

Keyword(s):

Rare Variant ◽

Principal Components ◽

Variance Components ◽

Rare Variant Analysis ◽

Variant Analysis

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Comparison of statistical approaches to rare variant analysis for quantitative traits

BMC Proceedings ◽

10.1186/1753-6561-5-s9-s113 ◽

2011 ◽

Vol 5 (S9) ◽

Cited By ~ 5

Author(s):

Han Chen ◽

Audrey E Hendricks ◽

Yansong Cheng ◽

Adrienne L Cupples ◽

Josée Dupuis ◽

...

Keyword(s):

Rare Variant ◽

Quantitative Traits ◽

Rare Variant Analysis ◽

Statistical Approaches ◽

Variant Analysis

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A unified method for rare variant analysis of gene‐environment interactions

Statistics in Medicine ◽

10.1002/sim.8446 ◽

2019 ◽

Vol 39 (6) ◽

pp. 801-813 ◽

Cited By ~ 2

Author(s):

Elise Lim ◽

Han Chen ◽

Josée Dupuis ◽

Ching‐Ti Liu

Keyword(s):

Rare Variant ◽

Rare Variant Analysis ◽

Gene Environment ◽

Variant Analysis ◽

Unified Method

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Small sample properties of rare variant analysis methods

BMC Proceedings ◽

10.1186/1753-6561-8-s1-s13 ◽

2014 ◽

Vol 8 (S1) ◽

Cited By ~ 1

Author(s):

Michael D Swartz ◽

Taebeom Kim ◽

Jiangong Niu ◽

Robert K Yu ◽

Sanjay Shete ◽

...

Keyword(s):

Rare Variant ◽

Small Sample ◽

Rare Variant Analysis ◽

Analysis Methods ◽

Small Sample Properties ◽

Variant Analysis

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380 Exome sequencing and rare variant analysis reveals multiple filaggrin mutations in Bangladeshi atopic eczema families and novel risk genes

Journal of Investigative Dermatology ◽

10.1016/j.jid.2016.02.413 ◽

2016 ◽

Vol 136 (5) ◽

pp. S67

Author(s):

M. Pigors ◽

J.E. Common ◽

C. Wong ◽

S. Malik ◽

C.A. Scott ◽

...

Keyword(s):

Exome Sequencing ◽

Rare Variant ◽

Atopic Eczema ◽

Risk Genes ◽

Rare Variant Analysis ◽

Variant Analysis

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Exome-wide Rare Variant Analysis Identifies TUBA4A Mutations Associated with Familial ALS

Neuron ◽

10.1016/j.neuron.2014.09.027 ◽

2014 ◽

Vol 84 (2) ◽

pp. 324-331 ◽

Cited By ~ 192

Author(s):

Bradley N. Smith ◽

Nicola Ticozzi ◽

Claudia Fallini ◽

Athina Soragia Gkazi ◽

Simon Topp ◽

...

Keyword(s):

Rare Variant ◽

Rare Variant Analysis ◽

Familial Als ◽

Variant Analysis

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A Bayesian method for rare variant analysis using functional annotations and its application to Autism

10.1101/828061 ◽

2019 ◽

Author(s):

Shengtong Han ◽

Nicholas Knoblauch ◽

Gao Wang ◽

Siming Zhao ◽

Yuwen Liu ◽

...

Keyword(s):

Rare Variant ◽

Bayesian Method ◽

Rare Variants ◽

External Information ◽

Risk Genes ◽

Prior Probabilities ◽

Functional Connections ◽

Rare Variant Analysis ◽

Risk Variants ◽

Variant Analysis

AbstractRare genetic variants make significant contributions to human diseases. Compared to common variants, rare variants have larger effect sizes and are generally free of linkage disequilibrium (LD), which makes it easier to identify causal variants. Numerous methods have been developed to analyze rare variants in a gene or region in association studies, with the goal of finding risk genes by aggregating information of all variants of a gene. These methods, however, often make unrealistic assumptions, e.g. all rare variants in a risk gene would have non-zero effects. In practice, current methods for gene-based analysis often fail to show any advantage over simple single-variant analysis. In this work, we develop a Bayesian method: MIxture model based Rare variant Analysis on GEnes (MIRAGE). MIRAGE captures the heterogeneity of variant effects by treating all variants of a gene as a mixture of risk and non-risk variants, and models the prior probabilities of being risk variants as function of external information of variants, such as allele frequencies and predicted deleterious effects. MIRAGE uses an empirical Bayes approach to estimate these prior probabilities by combining information across genes. We demonstrate in both simulations and analysis of an exome-sequencing dataset of Autism, that MIRAGE significantly outperforms current methods for rare variant analysis. In particular, the top genes identified by MIRAGE are highly enriched with known or plausible Autism risk genes. Our results highlight several novel Autism genes with high Bayesian posterior probabilities and functional connections with Autism. MIRAGE is available at https://xinhe-lab.github.io/mirage.

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Rare variant analysis of 4,241 pulmonary arterial hypertension cases from an international consortium implicate FBLN2, PDGFD and rare de novo variants in PAH

10.1101/2020.05.29.124255 ◽

2020 ◽

Cited By ~ 2

Author(s):

Na Zhu ◽

Emilia M. Swietlik ◽

Carrie L. Welch ◽

Michael W. Pauciulo ◽

Jacob J. Hagen ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Candidate Genes ◽

Rare Variant ◽

De Novo ◽

Risk Genes ◽

International Consortium ◽

Rare Variant Analysis ◽

Pulmonary Arterial ◽

Variant Analysis

AbstractBackgroundGroup 1 pulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by pathogenic remodeling of pulmonary arterioles leading to increased pulmonary pressures, right ventricular hypertrophy and heart failure. Recent high-throughput sequencing studies have identified additional PAH risk genes and suggested differences in genetic causes by age of onset. However, known risk genes explain only 15-20% of non-familial idiopathic PAH cases.MethodsTo identify new risk genes, we utilized an international consortium of 4,241 PAH cases with 4,175 sequenced exomes (n=2,572 National Biological Sample and Data Repository for PAH; n=469 Columbia University Irving Medical Center, enriched for pediatric trios) and 1,134 sequenced genomes (UK NIHR Bioresource – Rare Diseases Study). Most of the cases were adult-onset disease (93%), and 55% idiopathic (IPAH) and 35% associated with other diseases (APAH). We identified protein-coding variants and performed rare variant association analyses in unrelated participants of European ancestry, including 2,789 cases and 18,819 controls (11,101 unaffected parents from the Simons Powering Autism Research for Knowledge study and 7,718 gnomAD individuals). We analyzed de novo variants in 124 pediatric trios.ResultsSeven genes with rare deleterious variants were significantly associated (false discovery rate <0.1) with IPAH, including three known genes (BMPR2, GDF2, and TBX4), two recently identified candidate genes (SOX17, KDR), and two new candidate genes (FBLN2, fibulin 2; PDGFD, platelet-derived growth factor D). The candidate genes exhibit expression patterns in lung and heart similar to that of known PAH risk genes, and most of the variants occur in conserved protein domains. Variants in known PAH gene, ACVRL1, showed association with APAH. Predicted deleterious de novo variants in pediatric cases exhibited a significant burden compared to the background mutation rate (2.5x, p=7.0E-6). At least eight novel candidate genes carrying de novo variants have plausible roles in lung/heart development.ConclusionsRare variant analysis of a large international consortium identifies two new candidate genes - FBLN2 and PDGFD. The new genes have known functions in vasculogenesis and remodeling but have not been previously implicated in PAH. Trio analysis predicts that ~15% of pediatric IPAH may be explained by de novo variants.

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