Genome-wide linkage analysis of families with primary hyperhidrosis

PLoS One. 2020 Dec 30;15(12):e0244565. doi: 10.1371/journal.pone.0244565. eCollection 2020.

Abstract

Primary focal hyperhidrosis (PFH, OMIM %144110) is a genetically influenced condition characterised by excessive sweating. Prevalence varies between 1.0-6.1% in the general population, dependent on ethnicity. The aetiology of PFH remains unclear but an autosomal dominant mode of inheritance, incomplete penetrance and variable phenotypes have been reported. In our study, nine pedigrees (50 affected, 53 non-affected individuals) were included. Clinical characterisation was performed at the German Hyperhidrosis Centre, Munich, by using physiological and psychological questionnaires. Genome-wide parametric linkage analysis with GeneHunter was performed based on the Illumina genome-wide SNP arrays. Haplotypes were constructed using easyLINKAGE and visualised via HaploPainter. Whole-exome sequencing (WES) with 100x coverage in 31 selected members (24 affected, 7 non-affected) from our pedigrees was achieved by next generation sequencing. We identified four genome-wide significant loci, 1q41-1q42.3, 2p14-2p13.3, 2q21.2-2q23.3 and 15q26.3-15q26.3 for PFH. Three pedigrees map to a shared locus at 2q21.2-2q23.3, with a genome-wide significant LOD score of 3.45. The chromosomal region identified here overlaps with a locus at chromosome 2q22.1-2q31.1 reported previously. Three families support 1q41-1q42.3 (LOD = 3.69), two families share a region identical by descent at 2p14-2p13.3 (LOD = 3.15) and another two families at 15q26.3 (LOD = 3.01). Thus, our results point to considerable genetic heterogeneity. WES did not reveal any causative variants, suggesting that variants or mutations located outside the coding regions might be involved in the molecular pathogenesis of PFH. We suggest a strategy based on whole-genome or targeted next generation sequencing to identify causative genes or variants for PFH.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromosome Mapping / methods*
  • Exome Sequencing
  • Female
  • Genetic Linkage
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study / methods*
  • Germany
  • Haplotypes
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Hyperhidrosis / genetics*
  • Male
  • Pedigree
  • Polymorphism, Single Nucleotide*

Grants and funding

This work was supported by grants from the Luxembourg National Research Fund (FNR) within the National Centre for Excellence in Research on Parkinson’s disease (NCER-PD to DRB, PM), the EU Joint Program-Neurodegenerative Diseases (JPND; COURAGE-PD to DRB, PM), by the European Union’s Horizon2020 research and innovation program under grant agreement No 692320 (WIDESPREAD; CENTRE-PD to PM). The Research Fund of the University of Trier provided initial funding of the study to JM. Parts of the computational work in this study were performed on the highperformance cluster of the University of Luxembourg (https://hpc.uni.lu). Further funding was provided by the Alexander von Humboldt Postdoctoral Fellowship programme to ET, and the State Graduate Sponsorship Program of the State Rhineland-Palatinate to KG. JM and ABS were supported by the University Research Priority Program "Psychobiology of Stress" funded by the State Rhineland-Palatinate. The APC was funded by the Open Access Fund of Trier University and the German Research Foundation (DFG) within the Open Access Publishing funding program. DRB is an employee of Megeno S.A. Megeno S.A. provided support in the form of salaries for authors [DRB], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.