@article {128, title = {A phenome-wide association study of 26 mendelian genes reveals phenotypic expressivity of common and rare variants within the general population.}, journal = {PLoS Genet}, volume = {16}, year = {2020}, month = {2020 11}, pages = {e1008802}, abstract = {

The clinical evaluation of a genetic syndrome relies upon recognition of a characteristic pattern of signs or symptoms to guide targeted genetic testing for confirmation of the diagnosis. However, individuals displaying a single phenotype of a complex syndrome may not meet criteria for clinical diagnosis or genetic testing. Here, we present a phenome-wide association study (PheWAS) approach to systematically explore the phenotypic expressivity of common and rare alleles in genes associated with four well-described syndromic diseases (Alagille (AS), Marfan (MS), DiGeorge (DS), and Noonan (NS) syndromes) in the general population. Using human phenotype ontology (HPO) terms, we systematically mapped 60 phenotypes related to AS, MS, DS and NS in 337,198 unrelated white British from the UK Biobank (UKBB) based on their hospital admission records, self-administrated questionnaires, and physiological measurements. We performed logistic regression adjusting for age, sex, and the first 5 genetic principal components, for each phenotype and each variant in the target genes (JAG1, NOTCH2 FBN1, PTPN1 and RAS-opathy genes, and genes in the 22q11.2 locus) and performed a gene burden test. Overall, we observed multiple phenotype-genotype correlations, such as the association between variation in JAG1, FBN1, PTPN11 and SOS2 with diastolic and systolic blood pressure; and pleiotropy among multiple variants in syndromic genes. For example, rs11066309 in PTPN11 was significantly associated with a lower body mass index, an increased risk of hypothyroidism and a smaller size for gestational age, all in concordance with NS-related phenotypes. Similarly, rs589668 in FBN1 was associated with an increase in body height and blood pressure, and a reduced body fat percentage as observed in Marfan syndrome. Our findings suggest that the spectrum of associations of common and rare variants in genes involved in syndromic diseases can be extended to individual phenotypes within the general population.

}, keywords = {Alagille Syndrome, Alleles, Biological Variation, Population, DiGeorge Syndrome, European Continental Ancestry Group, Female, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Testing, Genetic Variation, Genome-Wide Association Study, Humans, Male, Marfan Syndrome, Noonan Syndrome, Phenotype, Polymorphism, Single Nucleotide, United Kingdom}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1008802}, author = {Tcheandjieu, Catherine and Aguirre, Matthew and Gustafsson, Stefan and Saha, Priyanka and Potiny, Praneetha and Haendel, Melissa and Ingelsson, Erik and Rivas, Manuel A and Priest, James R} } @article {66, title = {Components of genetic associations across 2,138 phenotypes in the UK Biobank highlight adipocyte biology.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 Sep 06}, pages = {4064}, abstract = {

Population-based biobanks with genomic and dense phenotype data provide opportunities for generating effective therapeutic hypotheses and understanding the genomic role in disease predisposition. To characterize latent components of genetic associations, we apply truncated singular value decomposition (DeGAs) to matrices of summary statistics derived from genome-wide association analyses across 2,138 phenotypes measured in 337,199 White British individuals in the UK Biobank study. We systematically identify key components of genetic associations and the contributions of variants, genes, and phenotypes to each component. As an illustration of the utility of the approach to inform downstream experiments, we report putative loss of function variants, rs114285050 (GPR151) and rs150090666 (PDE3B), that substantially contribute to obesity-related traits and experimentally demonstrate the role of these genes in adipocyte biology. Our approach to dissect components of genetic associations across the human phenome will accelerate biomedical hypothesis generation by providing insights on previously unexplored latent structures.

}, issn = {2041-1723}, doi = {10.1038/s41467-019-11953-9}, author = {Tanigawa, Yosuke and Li, Jiehan and Justesen, Johanne M and Horn, Heiko and Aguirre, Matthew and DeBoever, Christopher and Chang, Chris and Narasimhan, Balasubramanian and Lage, Kasper and Hastie, Trevor and Park, Chong Y and Bejerano, Gill and Ingelsson, Erik and Rivas, Manuel A} } @article {63, title = {Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts.}, journal = {Nat Med}, volume = {25}, year = {2019}, month = {2019 06}, pages = {911-919}, abstract = {

It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene. The current molecular diagnostic rate is estimated at 50\%, with whole-exome sequencing (WES) among the most successful approaches. For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases. This includes muscle biopsies from patients with undiagnosed rare muscle disorders, and cultured fibroblasts from patients with mitochondrial disorders. However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5\% diagnostic rate, and an additional 16.7\% with improved candidate gene resolution.

}, keywords = {Acid Ceramidase, Case-Control Studies, Child, Child, Preschool, Cohort Studies, Female, Genetic Variation, Humans, Male, Models, Genetic, Mutation, Oxidoreductases Acting on CH-CH Group Donors, Potassium Channels, Rare Diseases, RNA, RNA Splicing, Sequence Analysis, RNA, Whole Exome Sequencing}, issn = {1546-170X}, doi = {10.1038/s41591-019-0457-8}, author = {Fr{\'e}sard, Laure and Smail, Craig and Ferraro, Nicole M and Teran, Nicole A and Li, Xin and Smith, Kevin S and Bonner, Devon and Kernohan, Kristin D and Marwaha, Shruti and Zappala, Zachary and Balliu, Brunilda and Davis, Joe R and Liu, Boxiang and Prybol, Cameron J and Kohler, Jennefer N and Zastrow, Diane B and Reuter, Chloe M and Fisk, Dianna G and Grove, Megan E and Davidson, Jean M and Hartley, Taila and Joshi, Ruchi and Strober, Benjamin J and Utiramerur, Sowmithri and Lind, Lars and Ingelsson, Erik and Battle, Alexis and Bejerano, Gill and Bernstein, Jonathan A and Ashley, Euan A and Boycott, Kym M and Merker, Jason D and Wheeler, Matthew T and Montgomery, Stephen B} } @article {28, title = {Medical relevance of protein-truncating variants across 337,205 individuals in the UK Biobank study.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 Apr 24}, pages = {1612}, abstract = {

Protein-truncating variants can have profound effects on gene function and are critical for clinical genome interpretation and generating therapeutic hypotheses, but their relevance to medical phenotypes has not been systematically assessed. Here, we characterize the effect of 18,228 protein-truncating variants across 135 phenotypes from the UK Biobank and find 27 associations between medical phenotypes and protein-truncating variants in genes outside the major histocompatibility complex. We perform phenome-wide analyses and directly measure the effect in homozygous carriers, commonly referred to as "human knockouts," across medical phenotypes for genes implicated as being protective against disease or associated with at least one phenotype in our study. We find several genes with strong pleiotropic or non-additive effects. Our results illustrate the importance of protein-truncating variants in a variety of diseases.

}, keywords = {Databases, Nucleic Acid, Genome-Wide Association Study, Humans, Phenotype, Proteins, Sequence Deletion, United Kingdom}, issn = {2041-1723}, doi = {10.1038/s41467-018-03910-9}, author = {DeBoever, Christopher and Tanigawa, Yosuke and Lindholm, Malene E and McInnes, Greg and Lavertu, Adam and Ingelsson, Erik and Chang, Chris and Ashley, Euan A and Bustamante, Carlos D and Daly, Mark J and Rivas, Manuel A} }