Dataset Information

Exome Chip Analysis Identifies Low-Frequency and Rare Variants in MRPL38 for White Matter Hyperintensities on Brain Magnetic Resonance Imaging.

ABSTRACT: Background and Purpose- White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored. Methods- In the discovery sample we recruited 20?719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17?790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ?250?000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies. Results- At 17q25, we confirmed the association of multiple common variants in TRIM65, FBF1, and ACOX1 ( P<6×10-7). We also identified a novel association with 2 low-frequency nonsynonymous variants in MRPL38 (lead, rs34136221; PEA=4.5×10-8) partially independent of known common signal ( PEA(conditional)=1.4×10-3). We further identified a locus at 2q33 containing common variants in NBEAL1, CARF, and WDR12 (lead, rs2351524; Pall=1.9×10-10). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency MRPL38 variants ( Prs34136221=2.8×10-8). Conclusions- Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.

SUBMITTER: Jian X

PROVIDER: S-EPMC6202149 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Exome Chip Analysis Identifies Low-Frequency and Rare Variants in MRPL38 for White Matter Hyperintensities on Brain Magnetic Resonance Imaging.

Jian Xueqiu X Satizabal Claudia L CL Smith Albert V AV Wittfeld Katharina K Bis Joshua C JC Smith Jennifer A JA Hsu Fang-Chi FC Nho Kwangsik K Hofer Edith E Hagenaars Saskia P SP Nyquist Paul A PA Mishra Aniket A Adams Hieab H H HHH Li Shuo S Teumer Alexander A Zhao Wei W Freedman Barry I BI Saba Yasaman Y Yanek Lisa R LR Chauhan Ganesh G van Buchem Mark A MA Cushman Mary M Royle Natalie A NA Bryan R Nick RN Niessen Wiro J WJ Windham Beverly G BG DeStefano Anita L AL Habes Mohamad M Heckbert Susan R SR Palmer Nicholette D ND Lewis Cora E CE Eiriksdottir Gudny G Maillard Pauline P Mathias Rasika A RA Homuth Georg G Valdés-Hernández Maria Del C MDC Divers Jasmin J Beiser Alexa S AS Langner Sönke S Rice Kenneth M KM Bastin Mark E ME Yang Qiong Q Maldjian Joseph A JA Starr John M JM Sidney Stephen S Risacher Shannon L SL Uitterlinden André G AG Gudnason Vilmundur G VG Nauck Matthias M Rotter Jerome I JI Schreiner Pamela J PJ Boerwinkle Eric E van Duijn Cornelia M CM Mazoyer Bernard B von Sarnowski Bettina B Gottesman Rebecca F RF Levy Daniel D Sigurdsson Sigurdur S Vernooij Meike W MW Turner Stephen T ST Schmidt Reinhold R Wardlaw Joanna M JM Psaty Bruce M BM Mosley Thomas H TH DeCarli Charles S CS Saykin Andrew J AJ Bowden Donald W DW Becker Diane M DM Deary Ian J IJ Schmidt Helena H Kardia Sharon L R SLR Ikram M Arfan MA Debette Stéphanie S Grabe Hans J HJ Longstreth W T WT Seshadri Sudha S Launer Lenore J LJ Fornage Myriam M

Stroke 20180801 8

Background and Purpose- White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored. Methods- In the discovery sample we recruited 20 719 stroke/dementia ...[more]

PMID: 30002152

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Project description: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.

Project description:White matter hyperintensities of presumed vascular origin are frequently observed on magnetic resonance imaging in normal aging. They are typically found in cerebral small vessel disease and suspected culprits in the etiology of complex age- and small vessel disease-related conditions, such as late-onset depression. White matter hyperintensities may interfere with surrounding white matter metabolic demands by disrupting fiber tract integrity. Meanwhile, risk factors for small vessel disease are thought to reduce tissue oxygenation, not only by reducing regional blood supply, but also by impairing capillary function. To address white matter oxygen supply-demand balance, we estimated voxel-wise capillary density as an index of resting white matter metabolism, and combined estimates of blood supply and capillary function to calculate white matter oxygen availability. We conducted a cross-sectional study with structural, perfusion- and diffusion-weighted magnetic resonance imaging in 21 patients with late-onset depression and 21 controls. We outlined white matter hyperintensities and used tractography to identify the tracts they intersect. Perfusion data comprised cerebral blood flow, blood volume, mean transit time and relative transit time heterogeneity-the latter a marker of capillary dysfunction. Based on these, white matter oxygenation was calculated as the steady state cerebral metabolic rate of oxygen under the assumption of normal tissue oxygen tension and vice versa. The number, volume and perfusion characteristics of white matter hyperintensities did not differ significantly between groups. Hemodynamic data showed white matter hyperintensities to have lower blood flow and blood volume, but higher relative transit time heterogeneity, than normal-appearing white matter, resulting in either reduced capillary metabolic rate of oxygen or oxygen tension. Intersected tracts showed significantly lower blood flow, blood volume and capillary metabolic rate of oxygen than normal-appearing white matter. Across groups, lower lesion oxygen tension was associated with higher lesion number and volume. Compared with normal-appearing white matter, tissue oxygenation is significantly reduced in white matter hyperintensities as well as the fiber tracts they intersect, independent of parallel late-onset depression. In white matter hyperintensities, reduced microvascular blood volume and concomitant capillary dysfunction indicate a severe oxygen supply-demand imbalance with hypoxic tissue injury. In intersected fiber tracts, parallel reductions in oxygenation and microvascular blood volume are consistent with adaptations to reduced metabolic demands. We speculate, that aging and vascular risk factors impair white matter hyperintensity perfusion and capillary function to create hypoxic tissue injury, which in turn affect the function and metabolic demands of the white matter tracts they disrupt.

Dataset Information

Exome Chip Analysis Identifies Low-Frequency and Rare Variants in MRPL38 for White Matter Hyperintensities on Brain Magnetic Resonance Imaging.

Publications

Exome Chip Analysis Identifies Low-Frequency and Rare Variants in MRPL38 for White Matter Hyperintensities on Brain Magnetic Resonance Imaging.

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