Abstract

Introduction Extreme early-onset hypertension (EEHTN) defines a cohort of patients with a persistent blood pressure above 160/100mmHg under 30 years of age. This cohort is at heightened risk of complications and often undergo a diagnostic odyssey. We used Whole Genome Sequencing (WGS) data provided by the 100,000 Genomes Project (100KGP), to quantify the genetic contributors to EEHTN and to ascertain the diagnostic utility of WGS.

Methods We performed sequencing-based genome-wide association studies (GWAS) in 901 unrelated EEHTN cases and 20852 ancestry matched unaffected controls. The analysis was inclusive of individuals with diverse genetic ancestry. Enrichment of common, low-frequency minor allele frequency (MAF) > 0.1% and rare (MAF < 0.1%) single-nucleotide variant (SNV), insertion/deletion variants (indels) and rare structural variant (SV) alleles on a genome-wide and per-gene basis was sought using a generalised linear mixed model approach to account for population structure. A validated polygenic risk score (PRS) for hypertension (HTN) was applied to the EEHTN cohort and a primary HTN cohort.

Results Analysis of rare SNVs and indels revealed PKD1 (P=2.70 x 10-13) as significantly associated with EEHTN. This signal was lost when we excluded those with known renal disease. 81.5% of the individuals harbouring qualifying PKD1 variants had known cystic kidney disease (CyKD), this is replicated in the UK Biobank (UKBB). There were no common SNVs or rare SV associations with EEHTN. PRS discriminated between cases and controls (P = 2.2x10-16) but not between patients with PHTN or secondary HTN.

Conclusions These findings represent a thorough examination of the genetic architecture of a national EEHTN cohort using well-controlled statistical methodology. The low diagnostic yield of WGS in this group brings into question its utility as a population level clinical tool but provides insights into EEHTN biology. The PRS findings suggest shared genetic contributors to early-onset extreme hypertension and primary hypertension ascertained at any age.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This study did not receive any funding

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The study used only openly available human data that were originally part of The 100,000 Genomes Project

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Non-standard Abbreviations and Acronyms100KGP100,000 Genomes ProjectACMGAmerican College of Molecular Genetics and GenomicsADPKDAutosomal Dominant Polycystic Kidney DiseaseAggVCFAggregated Variant Calling FileBNDTranslocation Break-EndCADDCombined Annotation-Dependent DepletionCAKUTCongenital Anomalies of the Kidney and Urinary TractCNVCopy Number VariantCyKDCystic Kidney DiseaseDELDeletionDUPDuplicationEEHTNExtreme early-onset hypertensionFDRFalse Discovery RategVCFGenomic Variant Calling FileGMCGenomic Medicine CentreGWASGenome-Wide Association StudyHESHospital Episode StatisticsHPOHuman Phenotype OntologyHTNHypertensionIndelInsertion/Deletion VariantINSInsertionINVInversionKINGKinship-based Inference for Genome-wide association studiesLoFLoss of FunctionLOHLoss of HeterozygosityMAFMinor Allele FrequencyNHSNational Health ServicePHTNPrimary HypertensionPKDPolycystic Kidney DiseasePRSPolygenic Risk ScoreQ-Q plotQuantile-Quantile plotRR-EEHTNHospital Episode Statistics generated cohort without patients with known renal conditionsSAIGEScalable and Accurate Implementation of Generalized mixed modelSNVSingle Nucleotide VariantSVStructural VariantUKBBUK BiobankWGSWhole Genome Sequencing