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| Open AccessA method to estimate the contribution of rare coding variants to complex trait heritability
The contribution of rare variants to complex traits has not been well studied. Here, the authors present RARity, a method to assess rare variant heritability without assuming a particular genetic architecture and enabling both gene-level and exome-wide heritability estimation of continuous traits.
- Nazia Pathan
- , Wei Q. Deng
- & Guillaume Paré
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Article
| Open AccessSystematic analysis of paralogous regions in 41,755 exomes uncovers clinically relevant variation
Chameleolyser enables the accurate identification of genetic variants hidden within complex regions of the genome. Its application uncovers the disease-explanatory variant in 25 previously undiagnosed patients.
- Wouter Steyaert
- , Lonneke Haer-Wigman
- & Christian Gilissen
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Comment
| Open AccessUnravelling the genetic architecture of human complex traits through whole genome sequencing
Whole genome sequencing has enabled new insights into the genetic architecture of complex traits, especially through access to low-frequency and rare variation. This Comment highlights the key contributions from this technology and discusses considerations for its use and future perspectives.
- Ozvan Bocher
- , Cristen J. Willer
- & Eleftheria Zeggini
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Article
| Open AccessDirect haplotype-resolved 5-base HiFi sequencing for genome-wide profiling of hypermethylation outliers in a rare disease cohort
HiFi genome sequencing accesses DNA methylation and nucleotide variation in long sequence reads. Here, the authors apply this approach in a rare disease cohort to identify DNA hypermethylation linked to genetic variants including rare disease alleles.
- Warren A. Cheung
- , Adam F. Johnson
- & Tomi Pastinen
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Article
| Open AccessWhole-exome sequencing study identifies rare variants and genes associated with intraocular pressure and glaucoma
Elevated intraocular pressure is a risk factor for glaucoma. Here, the authors performed an exome-wide association study for intraocular pressure, demonstrating the power of rare variants in gene discovery and uncovering potential therapeutic targets for glaucoma.
- Xiaoyi Raymond Gao
- , Marion Chiariglione
- & Alexander J. Arch
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Article
| Open AccessThe contribution of common and rare genetic variants to variation in metabolic traits in 288,137 East Asians
Metabolic traits are heritable intermediate phenotypes widely used in assessing the risk of various diseases. By conducting a genome-wide meta-analysis for metabolic traits in 288,137 East Asians, the authors highlight the interplay of common and rare variants on inherited risk of metabolic traits.
- Young Jin Kim
- , Sanghoon Moon
- & Bong-Jo Kim
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Article
| Open AccessExtreme purifying selection against point mutations in the human genome
Previous work has investigated selection in the coding genome, but it is not as well characterized in the non-coding genome. By analyzing rare variants in 70k genome sequences from gnomAD, the authors detect very strong purifying selection ("ultraselection”) across the human genome, finding it in some microRNAs and coding sequences but generally rare in regulatory sequences.
- Noah Dukler
- , Mehreen R. Mughal
- & Adam Siepel
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Article
| Open AccessThe impact of rare germline variants on human somatic mutation processes
The impact of germline variants on somatic alterations in cancer remains to be explored in large-scale datasets. Here, the authors study the association of rare germline variants with somatic mutational processes in more than 15,000 tumors, and reveal that damaging variants in newly-identifed genes are prevalent in the population.
- Mischan Vali-Pour
- , Solip Park
- & Fran Supek
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Article
| Open AccessWhole-genome sequencing of 1,171 elderly admixed individuals from Brazil
Whole genome sequencing (WGS) data on non-European and admixed individuals remains scarce. Here, the authors analyse WGS data from 1,171 admixed elderly Brazilians from a census cohort, characterising population-specific genetic variation and exploring the clinical utility of this expanded dataset.
- Michel S. Naslavsky
- , Marilia O. Scliar
- & Mayana Zatz
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Article
| Open AccessPopulation-level deficit of homozygosity unveils CPSF3 as an intellectual disability syndrome gene
While the consequences of homozygous loss of function variants have been studied, the effect of missense variants is less understood. Here, the authors identify pathogenic genotypes through an observed deficit of homozygous carriers of missense variants in a population, elucidating previously unexplained recessive disease and miscarriage.
- Gudny A. Arnadottir
- , Asmundur Oddsson
- & Kari Stefansson
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Article
| Open AccessRare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4
Genetic studies of eczema to date have mostly explored common genetic variation. Here, the authors perform a large meta-analysis for common and rare variants and discover 8 loci associated with eczema. Over 20% of the heritability of the condition is attributable to rare variants.
- Sarah Grosche
- , Ingo Marenholz
- & Young-Ae Lee
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Article
| Open AccessCalibrated rare variant genetic risk scores for complex disease prediction using large exome sequence repositories
Identifying associations of rare variants with disease is challenging due to small effect sizes, technical artefacts and population structure heterogeneity. Here, the authors present RV-EXCALIBER, a method that uses large summary-level exome data to robustly calibrate rare variant burden.
- Ricky Lali
- , Michael Chong
- & Guillaume Paré
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Article
| Open AccessContextualizing genetic risk score for disease screening and rare variant discovery
Genetic studies on complex traits have revealed a substantial role for common, small-effect polygenic burden and large-effect variants. Here, the authors investigate how these types of variation can inform disease risk stratification and prediction.
- Dan Zhou
- , Dongmei Yu
- & Eric R. Gamazon
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Article
| Open AccessIdentifying therapeutic drug targets using bidirectional effect genes
Prioritising genes as potential drug targets is challenging and often unsuccessful once testing efficacy in humans. Here, the authors propose an approach to identifying drug targets that uses evidence from gain- or loss-of-function mutations associated with bidirectional effects on phenotypes.
- Karol Estrada
- , Steven Froelich
- & Lon R. Cardon
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Article
| Open AccessGenome-wide rare variant analysis for thousands of phenotypes in over 70,000 exomes from two cohorts
Population-based association analyses of rare genetic variants with complex traits are limited by the availability of data from sufficiently large cohorts. Here, Cirulli et al. report gene-based collapsing analysis of exomes from 49,960 participants of the UK Biobank and 21,866 participants of the Healthy Nevada Project over a total of 4377 traits.
- Elizabeth T. Cirulli
- , Simon White
- & Nicole L. Washington
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Article
| Open AccessThe Medical Genome Reference Bank contains whole genome and phenotype data of 2570 healthy elderly
Healthspan and healthy aging are areas of research with potential socioeconomic impact. Here, the authors present the Medical Genome Reference Bank (MGRB) which consist of over 4,000 individuals aged 70 years and older without a history of the major age-related diseases and report on results from whole-genome sequencing and association analyses.
- Mark Pinese
- , Paul Lacaze
- & David M. Thomas
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Article
| Open AccessPredictive impact of rare genomic copy number variations in siblings of individuals with autism spectrum disorders
Siblings of those with autism spectrum disorder (ASD) have increased likelihood of ASD or related subclinical traits. Here, studying 253 ASD families, D’Abate et al. test the predictive value of genomic copy number variation involving ASD-associated loci, with confirmation in a second cohort.
- L. D’Abate
- , S. Walker
- & S. W. Scherer
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Article
| Open AccessQuantitating the epigenetic transformation contributing to cholesterol homeostasis using Gaussian process
How epigenetics coordinate with genetics to impact protein fitness is unknown. Here, using a Variation Spatial Profiling strategy and machine learning, the authors map HDAC impact on a full set of Niemann pick C1 disease variants to quantitate an unanticipated plasticity in central dogma.
- Chao Wang
- , Samantha M. Scott
- & William E. Balch
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Article
| Open AccessQuantifying the polygenic contribution to variable expressivity in eleven rare genetic disorders
Rare genetic disorders (RGDs) often exhibit significant clinical variability among affected individuals. Here, Oetjens et al. systematically study the contribution of common genetic variation to variable expressivity of RGDs and find it is frequently influenced by polygenic factors identified in genome-wide association studies of relevant traits.
- M. T. Oetjens
- , M. A. Kelly
- & D. H. Ledbetter
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Article
| Open AccessCharacterizing rare and low-frequency height-associated variants in the Japanese population
Thousands of genetic loci are known to associate with human height, but these are mainly based on studies in European ancestry populations. Here, Akiyama et al. construct a genotype reference panel for the Japanese population followed by GWAS and report 573 height associated variants in 191,787 Japanese.
- Masato Akiyama
- , Kazuyoshi Ishigaki
- & Yoichiro Kamatani
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Article
| Open AccessExtensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations
Low frequency coding single-nucleotide variants (SNVs) are predicted to disproportionately affect protein function. Here, the authors evaluate 2,009 missense SNVs across 2,185 protein-protein interactions using yeast two-hybrid and protein complementation assays and find that disruptive SNVs often occur in disease-associated genes.
- Robert Fragoza
- , Jishnu Das
- & Haiyuan Yu
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Article
| Open AccessComponents of genetic associations across 2,138 phenotypes in the UK Biobank highlight adipocyte biology
While many pleiotropic genetic loci have been identified, how they contribute to phenotypes across traits and diseases is unclear. Here, the authors propose decomposition of genetic associations (DeGAs), which uses singular value decomposition, to characterize the underlying latent structure of genetic associations of 2,138 phenotypes.
- Yosuke Tanigawa
- , Jiehan Li
- & Manuel A. Rivas
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Article
| Open AccessCohort-wide deep whole genome sequencing and the allelic architecture of complex traits
Rare genetic variants can contribute to complex traits but this contribution is not well understood. Here, the authors analyse deep whole genome sequencing data across 1457 individuals from an isolated Greek population and find association of rare variant burdens with cardiometabolic traits.
- Arthur Gilly
- , Daniel Suveges
- & Eleftheria Zeggini
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Article
| Open AccessA homozygous loss-of-function mutation leading to CYBC1 deficiency causes chronic granulomatous disease
Mutations in genes encoding NAPDH oxidase subunits are known to be causative for the primary immunodeficiency chronic granulomatous disease (CGD). Here, the authors identify CYBC1 mutations in patients with CGD and show that CYBC1 is important for formation of the NADPH complex and respiratory burst.
- Gudny A. Arnadottir
- , Gudmundur L. Norddahl
- & Kari Stefansson
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Article
| Open AccessDeep-coverage whole genome sequences and blood lipids among 16,324 individuals
Common genetic variants associated with plasma lipids have been extensively studied for a better understanding of common diseases. Here, the authors use whole-genome sequencing of 16,324 individuals to analyze rare variant associations and to determine their monogenic and polygenic contribution to lipid traits.
- Pradeep Natarajan
- , Gina M. Peloso
- & Sebastian Zoellner
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Article
| Open AccessAnalysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease
Examination of predicted loss-of-function (pLOF) genetic variants allows direct identification of genes with therapeutic potential. Here, Emdin et al. perform association analysis for 3759 pLOF variants with 24 traits and highlight protective variants against cardiometabolic and immune phenotypes.
- Connor A. Emdin
- , Amit V. Khera
- & Sekar Kathiresan
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Article
| Open AccessMedical relevance of protein-truncating variants across 337,205 individuals in the UK Biobank study
Protein-truncating variants (PTVs) are predicted to significantly affect a gene’s function and, thus, human traits. Here, DeBoever et al. systematically analyze PTVs in more than 300,000 individuals across 135 phenotypes and identify 27 associations between PTVs and medical conditions.
- Christopher DeBoever
- , Yosuke Tanigawa
- & Manuel A. Rivas
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Article
| Open AccessIdentification of rare sequence variation underlying heritable pulmonary arterial hypertension
Pulmonary arterial hypertension (PAH) is a rare lung disorder characterised by narrowing and obliteration of small pulmonary arteries ultimately leading to right heart failure. Here, the authors sequence whole genomes of over 1000 PAH patients and identify likely causal variants in GDF2, ATP13A3, AQP1 and SOX17.
- Stefan Gräf
- , Matthias Haimel
- & Nicholas W. Morrell
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Article
| Open AccessIntegrating evolutionary and regulatory information with a multispecies approach implicates genes and pathways in obsessive-compulsive disorder
Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder with symptoms including intrusive thoughts and time-consuming repetitive behaviors. Here Noh and colleagues identify genes enriched for functional variants associated with increased risk of OCD.
- Hyun Ji Noh
- , Ruqi Tang
- & Kerstin Lindblad-Toh
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Article
| Open AccessWhole genome sequencing and imputation in isolated populations identify genetic associations with medically-relevant complex traits
Isolated populations can provide useful information on low-frequency variants for dissecting genetic architecture of complex traits. Here, Zeggini and colleagues show enrichment of rare and low-frequency variants and 8 novel low-frequency variant signals for cardiometabolic traits in two Greek isolated populations
- Lorraine Southam
- , Arthur Gilly
- & Eleftheria Zeggini
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Article
| Open AccessUltrasensitive and high-efficiency screen of de novo low-frequency mutations by o2n-seq
Detection ofde novo, low frequency mutations is important for characterising heterogeneous cell populations, such as those found in cancer cell populations. Here the authors present o2n-seq, an ultrasensitive method with highly efficient data usage for detection of rare mutations.
- Kaile Wang
- , Shujuan Lai
- & Jue Ruan
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Article
| Open AccessDiverse genetic architectures lead to the same cryptic phenotype in a yeast cross
Cryptic genetic variants may not individually show discernible phenotypic effects, but collectively, these polymorphisms can lead to unexpected, genetically complex traits that might be relevant to evolution and disease. Here, the authors use large yeast populations to comprehensively dissect the genetic bases of 17 independent occurrences of a phenotype that arises due to combinations of epistatically interacting cryptic variants.
- Matthew B. Taylor
- , Joann Phan
- & Ian M. Ehrenreich
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Article
| Open AccessA uniform survey of allele-specific binding and expression over 1000-Genomes-Project individuals
Using variants from the 1000 Genomes Project, RNA-seq and ChIP-seq data from related projects, this study describes a resource and survey of allele-specific binding and gene expression. A catalogue of allelic SNPs and annotation elements is available as an online resource at alleledb.gersteinlab.org.
- Jieming Chen
- , Joel Rozowsky
- & Mark Gerstein
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Article
| Open AccessRare variant discovery by deep whole-genome sequencing of 1,070 Japanese individuals
The Tohoku Medical Megabank Organization establishes a biobank with detailed patient health care and genome information. Here the authors analyse whole-genome sequences of 1,070 Japanese individuals, allowing them to catalogue 21 million single-nucleotide variants including 12 million novel ones.
- Masao Nagasaki
- , Jun Yasuda
- & Masayuki Yamamoto
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Article
| Open AccessRare coding variants and X-linked loci associated with age at menarche
Previous studies have linked over 100 genomic loci to age-at-menarche but that work was restricted to common autosomal variation. Here, Lunetta et al. identify associations with rare protein-coding and X-linked variants, implicating new mechanisms that regulate puberty timing.
- Kathryn L. Lunetta
- , Felix R. Day
- & John R. B. Perry
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Article
| Open AccessGenome-wide burden of deleterious coding variants increased in schizophrenia
Schizophrenia is a complex disorder with high heritability but poorly understood genetics. Here Olde Loohuis et al.compare schizophrenia patients to unaffected individuals and identify an increased individual burden of rare deleterious mutations in patients.
- Loes M. Olde Loohuis
- , Jacob A. S. Vorstman
- & Roel A. Ophoff
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Article
| Open AccessTemporal regulation of kin recognition maintains recognition-cue diversity and suppresses cheating
It is unclear how variation in cues that enable recognition of kin and facilitate cooperation is maintained. Here, the authors show that rare variants of Dictyostelium discoideumare excluded from aggregates when the potential for social cheating is high, but subsequently rejoin the aggregate and produce spores.
- Hsing-I Ho
- & Gad Shaulsky
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Article
| Open AccessGenome of the Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels
Frequencies of rare variants fluctuate over populations, hampering gene discovery. Here the authors use a population-specific reference panel, the Genome of the Netherlands, to discover four novel loci involved in lipid metabolism, including an exonic variant in ABCA6.
- Elisabeth M. van Leeuwen
- , Lennart C. Karssen
- & Cornelia M. van Duijn
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Article
| Open AccessWhole-genome sequence-based analysis of thyroid function
Levels of circulating thyrotropin and free thyroxine reflect thyroid function, however, their genetic underpinnings remain poorly understood. Taylor et al. take advantage of whole-genome sequence data from cohorts within the UK10K project to identify novel variants associated with these traits.
- Peter N. Taylor
- , Eleonora Porcu
- & Pingbo Zhang
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Article
| Open AccessLow-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility
Both rare and common variants contribute to the aetiology of complex traits such as type 2 diabetes (T2D). Here, the authors examine the effect of coding variation on glycaemic traits and T2D, and identify low-frequency variation in GLP1Rsignificantly associated with these traits.
- Jennifer Wessel
- , Audrey Y Chu
- & Mark O Goodarzi
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Article
| Open AccessEthnic-specific associations of rare and low-frequency DNA sequence variants with asthma
Common variants account for only a small amount of the heritable risk for developing asthma. Using a meta-analysis approach, Igartua et al. identify one low-frequency missense mutation and two genes with functional variants that are associated with asthma, but only in specific ethnic groups.
- Catherine Igartua
- , Rachel A. Myers
- & Carole Ober
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Article
| Open AccessA rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans
Population-based genome sequencing provides an increasingly rich resource for the identification of low-frequency, large effect variants associated with clinically important phenotypes. Timpson et al. use UK10K data to identify a variant of the APOC3gene strongly associated with plasma triglyceride levels.
- Nicholas J. Timpson
- , Klaudia Walter
- & Hou-Feng Zheng
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Article
| Open AccessA rare functional cardioprotective APOC3 variant has risen in frequency in distinct population isolates
Isolated populations may empower genetic association studies of complex traits. Here, the authors identify a rare cardioprotective APOC3variant in a Greek population isolate and highlight the value of using population isolates to detect rare variants that confer disease risk.
- Ioanna Tachmazidou
- , George Dedoussis
- & Eleftheria Zeggini
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Article
| Open AccessDeep resequencing reveals excess rare recent variants consistent with explosive population growth
To fully catalogue rare genetic variation in humans, many samples need to be examined. In this study, Coventryet al. resequenced two genes, KCNJ11 and HHEX, in 13,715 humans, and concluded that most of the sequence variation arose recently and that variation is greater than expected.
- Alex Coventry
- , Lara M. Bull-Otterson
- & Charles F. Sing