Whole-exome sequencing reveals a role of HTRA1 and EGFL8 in brain white matter hyperintensities

Author:

Malik Rainer1ORCID,Beaufort Nathalie1,Frerich Simon1,Gesierich Benno1,Georgakis Marios K1ORCID,Rannikmäe Kristiina2ORCID,Ferguson Amy C2,Haffner Christof1ORCID,Traylor Matthew34ORCID,Ehrmann Michael56,Sudlow Cathie L M278ORCID,Dichgans Martin1910

Affiliation:

1. Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, 81377 Munich, Germany

2. Centre for Medical Informatics, Usher Institute, University of Edinburgh, Edinburgh EH16 4TL, UK

3. Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, UK

4. The Barts Heart Centre and NIHR Barts Biomedical Research Centre - Barts Health NHS Trust, The William Harvey Research Institute, Queen Mary University of London, London, UK

5. Center of Medical Biotechnology, Faculty of Biology, University Duisburg-Essen, Essen 45141, Germany

6. School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK

7. Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH16 4TL, UK

8. Health Data Research UK Scotland, University of Edinburgh, Edinburgh EH16 4TL, UK

9. Munich Cluster for Systems Neurology, Munich 81377, Germany

10. German Center for Neurodegenerative Diseases (DZNE), Munich 81377, Germany

Abstract

Abstract White matter hyperintensities (WMH) are among the most common radiological abnormalities in the ageing population and an established risk factor for stroke and dementia. While common variant association studies have revealed multiple genetic loci with an influence on their volume, the contribution of rare variants to the WMH burden in the general population remains largely unexplored. We conducted a comprehensive analysis of this burden in the UK Biobank using publicly available whole-exome sequencing data (n up to 17 830) and found a splice-site variant in GBE1, encoding 1,4-alpha-glucan branching enzyme 1, to be associated with lower white matter burden on an exome-wide level [c.691+2T>C, β = −0.74, standard error (SE) = 0.13, P = 9.7 × 10−9]. Applying whole-exome gene-based burden tests, we found damaging missense and loss-of-function variants in HTRA1 (frequency of 1 in 275 in the UK Biobank population) to associate with an increased WMH volume (P = 5.5 × 10−6, false discovery rate = 0.04). HTRA1 encodes a secreted serine protease implicated in familial forms of small vessel disease. Domain-specific burden tests revealed that the association with WMH volume was restricted to rare variants in the protease domain (amino acids 204–364; β = 0.79, SE = 0.14, P = 9.4 × 10−8). The frequency of such variants in the UK Biobank population was 1 in 450. The WMH volume was brought forward by ∼11 years in carriers of a rare protease domain variant. A comparison with the effect size of established risk factors for WMH burden revealed that the presence of a rare variant in the HTRA1 protease domain corresponded to a larger effect than meeting the criteria for hypertension (β = 0.26, SE = 0.02, P = 2.9 × 10−59) or being in the upper 99.8% percentile of the distribution of a polygenic risk score based on common genetic variants (β = 0.44, SE = 0.14, P = 0.002). In biochemical experiments, most (6/9) of the identified protease domain variants resulted in markedly reduced protease activity. We further found EGFL8, which showed suggestive evidence for association with WMH volume (P = 1.5 × 10−4, false discovery rate = 0.22) in gene burden tests, to be a direct substrate of HTRA1 and to be preferentially expressed in cerebral arterioles and arteries. In a phenome-wide association study mapping ICD-10 diagnoses to 741 standardized Phecodes, rare variants in the HTRA1 protease domain were associated with multiple neurological and non-neurological conditions including migraine with aura (odds ratio = 12.24, 95%CI: 2.54–35.25; P = 8.3 × 10−5]. Collectively, these findings highlight an important role of rare genetic variation and the HTRA1 protease in determining WMH burden in the general population.

Funder

European Union’s Horizon 2020 research and innovation programme

DFG

Munich Cluster for Systems Neurology

Fondation Leducq

Deutsche Forschungsgemeinschaft

Health data Research UK Rutherford fellowship

BHF

Publisher

Oxford University Press (OUP)

Subject

Neurology (clinical)

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