Dataset Information

Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4.

ABSTRACT: Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema.

SUBMITTER: Grosche S

PROVIDER: S-EPMC8595373 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4.

Grosche Sarah S Marenholz Ingo I Esparza-Gordillo Jorge J Arnau-Soler Aleix A Pairo-Castineira Erola E Rüschendorf Franz F Ahluwalia Tarunveer S TS Almqvist Catarina C Arnold Andreas A Baurecht Hansjörg H Bisgaard Hans H Bønnelykke Klaus K Brown Sara J SJ Bustamante Mariona M Curtin John A JA Custovic Adnan A Dharmage Shyamali C SC Esplugues Ana A Falchi Mario M Fernandez-Orth Dietmar D Ferreira Manuel A R MAR Franke Andre A Gerdes Sascha S Gieger Christian C Hakonarson Hakon H Holt Patrick G PG Homuth Georg G Hubner Norbert N Hysi Pirro G PG Jarvelin Marjo-Riitta MR Karlsson Robert R Koppelman Gerard H GH Lau Susanne S Lutz Manuel M Magnusson Patrik K E PKE Marks Guy B GB Müller-Nurasyid Martina M Nöthen Markus M MM Paternoster Lavinia L Pennell Craig E CE Peters Annette A Rawlik Konrad K Robertson Colin F CF Rodriguez Elke E Sebert Sylvain S Simpson Angela A Sleiman Patrick M A PMA Standl Marie M Stölzl Dora D Strauch Konstantin K Szwajda Agnieszka A Tenesa Albert A Thompson Philip J PJ Ullemar Vilhelmina V Visconti Alessia A Vonk Judith M JM Wang Carol A CA Weidinger Stephan S Wielscher Matthias M Worth Catherine L CL Xu Chen-Jian CJ Lee Young-Ae YA

Nature communications 20211116 1

Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In D ...[more]

PMID: 34785669

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Project description:BackgroundIntegrating rare variation from trio family and case-control studies has successfully implicated specific genes contributing to risk of neurodevelopmental disorders (NDDs) including autism spectrum disorders (ASD), intellectual disability (ID), developmental disorders (DDs), and epilepsy (EPI). For schizophrenia (SCZ), however, while sets of genes have been implicated through the study of rare variation, only two risk genes have been identified.MethodsWe used hierarchical Bayesian modeling of rare-variant genetic architecture to estimate mean effect sizes and risk-gene proportions, analyzing the largest available collection of whole exome sequence data for SCZ (1,077 trios, 6,699 cases, and 13,028 controls), and data for four NDDs (ASD, ID, DD, and EPI; total 10,792 trios, and 4,058 cases and controls).ResultsFor SCZ, we estimate there are 1,551 risk genes. There are more risk genes and they have weaker effects than for NDDs. We provide power analyses to predict the number of risk-gene discoveries as more data become available. We confirm and augment prior risk gene and gene set enrichment results for SCZ and NDDs. In particular, we detected 98 new DD risk genes at FDR < 0.05. Correlations of risk-gene posterior probabilities are high across four NDDs (ρ>0.55), but low between SCZ and the NDDs (ρ<0.3). An in-depth analysis of 288 NDD genes shows there is highly significant protein-protein interaction (PPI) network connectivity, and functionally distinct PPI subnetworks based on pathway enrichment, single-cell RNA-seq cell types, and multi-region developmental brain RNA-seq.ConclusionsWe have extended a pipeline used in ASD studies and applied it to infer rare genetic parameters for SCZ and four NDDs ( https://github.com/hoangtn/extTADA ). We find many new DD risk genes, supported by gene set enrichment and PPI network connectivity analyses. We find greater similarity among NDDs than between NDDs and SCZ. NDD gene subnetworks are implicated in postnatally expressed presynaptic and postsynaptic genes, and for transcriptional and post-transcriptional gene regulation in prenatal neural progenitor and stem cells.

Dataset Information

Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4.

Publications

Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4.

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