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Frequency of stroke/transient ischemic attack (TIA) and extracerebral phenotypes. HetZ indicates heterozygous; and HomZ, homozygous/compound heterozygous.
Source publication
Background and Purpose
An important minority of cerebral small vessel disease (cSVD) is monogenic. Many monogenic cSVD genes are recognized to be associated with extracerebral phenotypes. We assessed the frequency of these phenotypes in existing literature.
Methods
We performed a systematic review following the PRISMA guidelines (Preferred Reporti...
Contexts in source publication
Context 1
... frequency of specific extracerebral phenotypes ranged widely across genes: 3% to 19% for COL4A1; 0% to 68% for TREX1; 37% to 74% for HTRA1 HomZ ; 0% to 8% for COL4A2; 11% to 66% for ADA2; 7% to 31% for HTRA1 HetZ ; and 64% to 93% CTSA (Figure 4, Figure II in the Data Supplement). Detailed definitions of included phenotypes are available from Table I in the Data Supplement. ...
Context 2
... majority of COL4A1/2 strokes (73% [115/157] and 100% [21/21], respectively) were hemorrhagic, while ischemic stroke/TIA was more commonly reported for the other genes. Hemorrhagic stroke remained the most common stroke type for COL4A1/2 individuals when excluding those presenting only with porencephaly (Figure 4, Figure II in the Data Supplement). individuals. ...
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Background
Beat-to-beat blood pressure variability is associated with increased stroke risk but its importance at different ages is unclear.
Aims
To determine the age-sex distribution of blood pressure variability in patients with transient ischemic stroke or minor stroke.
Methods
In consecutive patients within six weeks of transient ischemic str...
Citations
... We also could not include 2 reviews assessing monogenic forms of cSVD because both based cSVD presence solely on genetic variants rather than neuroimaging features as per STRIVE-v1. 52,53 Notably, we did not include associations between cSVD features and clinical stroke syndromes in our synthesis. Our reasoning was twofold; such associations are well established and have been extensively published, and our primary intention was to shed light on less explored associations. ...
Background and objectives:
Cerebral small vessel disease (cSVD) causes lacunar and hemorrhagic stroke and is an important contributor to vascular cognitive impairment. Other potential physical and psychological consequences of cSVD have been described across various body systems. Descriptions of cSVD are available in journals specific to those individual body systems, but a comprehensive assessment of clinical manifestations across this disparate literature is lacking. We conducted an overview of systematic reviews describing clinical cSVD phenotypes.
Methods:
We searched multidisciplinary databases from inception to December 2023. We included reviews describing concurrent clinical phenotypes in individuals with neuroimaging evidence of cSVD, defined using the STandards for ReportIng Vascular changes on nEuroimaging criteria. We broadly classified phenotypes into cognitive, mood and neuropsychiatric, respiratory, cardiovascular, renal-urinary, peripheral nervous system, locomotor, and gastrointestinal. We included both studies assessing multiple cSVD features and studies examining individual cSVD markers. We extracted risk factor-adjusted effect estimates, where possible, and assessed methodologic quality using the Assessment of Multiple Systematic Reviews-2 tool.
Results:
After screening 6,156 publications, we included 24 systematic reviews reporting on 685 original studies and 1,135,943 participants. Cognitive and neuropsychiatric phenotypes were examined most often, particularly in relation to white matter hyperintensities (range of risk ratios [RRs] for cognitive phenotypes 1.21-1.49, range of 95% CI 1.01-1.84; for neuropsychiatric, RR 1.02-5.71, 95% CI 0.96-19.69). Two reviews focused solely on perivascular spaces. No reviews assessed lacunes or small subcortical infarcts separately from other cSVD features. Reviews on peripheral nervous system, urinary, or gastrointestinal phenotypes were lacking. Fourteen reviews had high methodologic quality, 5 had moderate quality, and 5 had low quality. Heterogeneity in cSVD definitions and phenotypic assessments was substantial.
Discussion:
Neuroimaging markers of cSVD are associated with various clinical manifestations, suggesting a multisystem phenotype. However, features classically associated with cSVD, for example, gait, had limited supporting evidence, and for many body systems, there were no available reviews. Similarly, while white matter hyperintensities were relatively well studied, there were limited data on phenotypes associated with other cSVD features. Future studies should characterize the full clinical spectrum of cSVD and explore clinical associations beyond neurocognitive and neuropsychiatric presentations.
... Clinically, COL4A1/A2 mutations cause a wide variety of phenotypes ranging from fetal death, porencephaly, and intracerebral hemorrhages to cerebral microangiopathy, cervical artery dissection, and some individuals even remain asymptomatic [10,16,17]. Extra-neurological features, such as renal involvement, cardiac involvement, and ocular disease, occur in a subset of variants [18]. PADMAL is caused by variants outside the protein-coding part of COL4A1, affecting a micro-RNA (miRNA-29)-binding site in the 3'-untranslated region (3'-UTR) [5][6][7][8][9]. ...
Background
(1) Description of clinical and cranial MRI features in the original Pontine Autosomal Dominant Microangiopathy with Leukoencephalopathy (PADMAL) family and correlation with the segregation analysis of the causative collagen 4A1 gene (COL4A1) variant. (2) Sequence analysis of the COL4A1 miRNA-binding site containing the causative variant in two independent cross-sectional samples of sporadic stroke patients.
Patients and methods
Sanger sequencing of the COL4A1 miRNA-binding site in the PADMAL family and 874 sporadic stroke patients.
Results
PADMAL shows adult-onset usually between 30 and 50 years of age with initial brainstem-related symptoms most commonly dysarthria, with progression to dementia and tetraparesis. Radiologically pontine lacunes are followed by supratentorial white matter involvement. Radiological onset may precede clinical symptoms. We found no variants in the COL4A1 miRNA-binding site of sporadic stroke patients.
Conclusion
Our results allow an early diagnosis of PADMAL based on cranial MRI, clinical signs, and confirmatory sequencing of the COL4A1 miRNA-29-binding site. COL4A1 miRNA-29-binding site variants do not contribute to a sizeable proportion of sporadic stroke.
... 2 Many monogenic cSVD cases also show overlapping systemic and neurologic features. 2,6,7 To date, our knowledge of monogenic cSVD variants' frequency, penetrance, and phenotype associations comes primarily from case reports, small case series, and family pedigree studies. 6 The resulting data are therefore affected by various biases, including investigation bias (patients with clinically severe and previously described manifestations are more likely to have genetic testing and undergo investigations for known expected associated pathologies if a pathogenic variant in a relevant gene is found), publication bias (clinicians/researchers are more likely to publish a case report/series about clinically severely and/or unusually affected patients), and reporting bias (published case reports/series tend to discuss previously reported or particularly unusual clinical signs and symptoms rather than describe case's health in an unbiased and systematic way). ...
... 2,6,7 To date, our knowledge of monogenic cSVD variants' frequency, penetrance, and phenotype associations comes primarily from case reports, small case series, and family pedigree studies. 6 The resulting data are therefore affected by various biases, including investigation bias (patients with clinically severe and previously described manifestations are more likely to have genetic testing and undergo investigations for known expected associated pathologies if a pathogenic variant in a relevant gene is found), publication bias (clinicians/researchers are more likely to publish a case report/series about clinically severely and/or unusually affected patients), and reporting bias (published case reports/series tend to discuss previously reported or particularly unusual clinical signs and symptoms rather than describe case's health in an unbiased and systematic way). 6,8,9 There have also been few disease-based studies exploring rare variation in cSVD genes in apparently sporadic cases of cSVD, [10][11][12][13] but the population frequency and clinical consequences of these variants remain unknown. ...
... 6 The resulting data are therefore affected by various biases, including investigation bias (patients with clinically severe and previously described manifestations are more likely to have genetic testing and undergo investigations for known expected associated pathologies if a pathogenic variant in a relevant gene is found), publication bias (clinicians/researchers are more likely to publish a case report/series about clinically severely and/or unusually affected patients), and reporting bias (published case reports/series tend to discuss previously reported or particularly unusual clinical signs and symptoms rather than describe case's health in an unbiased and systematic way). 6,8,9 There have also been few disease-based studies exploring rare variation in cSVD genes in apparently sporadic cases of cSVD, [10][11][12][13] but the population frequency and clinical consequences of these variants remain unknown. ...
Background and Objectives
Based on previous case reports and disease-based cohorts, a minority of patients with cerebral small vessel disease (cSVD) have a monogenic cause, with many also manifesting extracerebral phenotypes. We investigated the frequency, penetrance, and phenotype associations of putative pathogenic variants in cSVD genes in the UK Biobank (UKB), a large population-based study.
Methods
We used a systematic review of previous literature and ClinVar to identify putative pathogenic rare variants in CTSA , TREX1 , HTRA1 , and COL4A1/2 . We mapped phenotypes previously attributed to these variants (phenotypes-of-interest) to disease coding systems used in the UKB's linked health data from UK hospital admissions, death records, and primary care. Among 199,313 exome-sequenced UKB participants, we assessed the following: the proportion of participants carrying ≥1 variant(s); phenotype-of-interest penetrance; and the association between variant carrier status and phenotypes-of-interest using a binary (any phenotype present/absent) and phenotype burden (linear score of the number of phenotypes a participant possessed) approach.
Results
Among UKB participants, 0.5% had ≥1 variant(s) in studied genes. Using hospital admission and death records, 4%–20% of variant carriers per gene had an associated phenotype. This increased to 7%–55% when including primary care records. Only COL4A1 variant carrier status was significantly associated with having ≥1 phenotype-of-interest and a higher phenotype score (OR = 1.29, p = 0.006).
Discussion
While putative pathogenic rare variants in monogenic cSVD genes occur in 1:200 people in the UKB population, only approximately half of variant carriers have a relevant disease phenotype recorded in their linked health data. We could not replicate most previously reported gene-phenotype associations, suggesting lower penetrance rates, overestimated pathogenicity, and/or limited statistical power.
... 8 It has been reported that the frequency of extra-neurological manifestations in dominant CSVD is lower in patients with heterozygous missense mutations than in CARASIL. 19 In our study, patients with heterozygous HTRA1 mutations had a high frequency of spine disorders and a low frequency of alopecia, which is congruent with previous studies. 8,20 Intracranial arachnoid cyst is commonly considered a congenital lesion; it occurs most commonly in the temporal fossa and is relatively more prevalent in male patients. ...
Objective:
There is evidence showing both heterozygous HTRA1 and homozygous HTRA1 mutations as causal for familial cerebral small vessel disease (CSVD). The clinical and neuroimaging signs of heterozygous HTRA1-related CSVD can mimic cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We aimed to characterize the genotypic and phenotypic features of HTRA1-related CSVD, and we compared the features of heterozygous HTRA1-related CSVD and CADASIL.
Methods:
We carried out genetic sequencing in a series of unrelated patients with suspected familial CSVD from China. Clinical and imaging characteristics of heterozygous HTRA1-related CSVD and CADASIL were compared.
Results:
We identified nine heterozygous HTRA1 mutations and one homozygous HTRA1 mutation, seven of which are novel. Compared with CADASIL, patients with heterozygous HTRA1-related CSVD had a higher proportion of spine disorders and a lower proportion of white matter hyperintensities involving the anterior temporal lobe (p < 0.001).
Interpretation:
This study shows that most HTRA1-related CSVD patients in China carry heterozygous HTRA1 mutations. The specific extra-neurological features and neuroimaging features reveal informative differences between heterozygous HTRA1-related CSVD and CADASIL. We expand the mutational spectrum of HTRA1.
... However, since NOTCH3 was first described in 1996, several additional cSVD genes have been identified, including COL4A1, TREX1, HTRA1, COL4A2, ADA2 and, most recently, CTSA. Pathogenic rare variants in these genes have been associated with various clinical phenotypes alongside cSVD, including extracerebral manifestations, as well as certain radiological features seen on neuroimaging (5). ...
... We did not restrict the search by language or publication date; we limited it to human studies; we included conference abstracts. We used a previously-published search strategy (see Data Supplement) (5). In summary, the search included: ...
... The findings summarised here have potential clinical implications for the diagnosis and follow up of monogenic cSVDs, especially in conjunction with previous data of associated extracerebral phenotypes (5). Having said this, to get a more comprehensive and less biased overview of the clinical and radiological consequences of monogenic cSVDs, further work should address these same questions using a genotype-first approach (i.e., studying this in a population-based setting and among individuals selected based on carrying the variant of interest, regardless of their phenotype). ...
Background: Cerebral small vessel disease (cSVD) is an important cause of stroke and vascular dementia. Most cases are multifactorial, but an emerging minority have a monogenic cause. While NOTCH3 is the best-known gene, several others have been reported. We aimed to summarise the cerebral phenotypes associated with these more recent cSVD genes.
Methods: We performed a systematic review (PROSPERO: CRD42020196720), searching Medline/Embase (conception to July 2020) for any language publications describing COL4A1/2, TREX1, HTRA1, ADA2, or CTSA pathogenic variant carriers. We extracted data about individuals characteristics, clinical and vascular radiological cerebral phenotypes. We summarised phenotype frequencies per gene, comparing patterns across genes.
Results: We screened 6,485 publications including 402, and extracted data on 390 COL4A1, 123 TREX1, 44 HTRA1 homozygous, 41 COL4A2, 346 ADA2, 82 HTRA1 heterozygous, and 14 CTSA individuals. Mean age ranged from 15 (ADA2) to 59 years (HTRA1 heterozygotes). Clinical phenotype frequencies varied widely: stroke 9% (TREX1) to 52% (HTRA1 heterozygotes), cognitive features 0% (ADA2) to 64% (HTRA1 homozygotes), psychiatric features 0% (COL4A2; ADA2) to 57% (CTSA). Among individuals with neuroimaging, vascular radiological phenotypes appeared common, ranging from 62% (ADA2) to 100% (HTRA1 homozygotes; CTSA). White matter lesions were the most common pathology, except in ADA2 and COL4A2 cases, where ischaemic and haemorrhagic lesions dominated, respectively.
Conclusions: There appear to be differences in cerebral manifestations across cSVD genes. Vascular radiological changes were more common than clinical neurological phenotypes, and present in the majority of individuals with reported neuroimaging. However, these results may be affected by age and biases inherent to case reports. In the future, better characterisation of associated phenotypes, as well as insights from population-based studies, should improve our understanding of monogenic cSVD to inform genetic testing, guide clinical management, and help unravel underlying disease mechanisms.
... 24,25 Notably, extracerebral manifestations such as ocular and renal manifestations sometimes occur in rare forms of hereditary SVD. 26 While the above studies have contributed to the understanding of common genetic variation in WMH and the role of highly penetrant mutations in familial SVD, the significance of rare genetic variations for WMH in the general population remains largely unexplored. To the best of our knowledge, previous studies focused on variants included on HumanExome BeadChip arrays 27 and on genes implicated in familial SVD. ...
... Rare variants in the HTRA1 protease domain associate with multiple neurological and non-neurological phenotypes HTRA1 mutation carriers exhibit a wide range of cerebral and extracerebral phenotypes. 26 To comprehensively assess disease Genes reaching exome wide significance (FDR-adjusted P 5 0.05; in bold) or suggestive evidence (FDR-adjusted P 5 0.25) for an association with logWMH volume are listed. The results were derived from a unidirectional mutivariable burden test on logWMH and adjusted for age at imaging, sex and the first 10 genomic principal components. ...
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.
... 3 The frequency of extra-neurological manifestations in this dominant CSVD has been reported to be lower in heterozygous missense patients than in CARASIL. 5 Its clinical phenotype is quite similar to sporadic CSVD with the exception of its familial nature. In vitro transfection experiments showed that most HTRA1 heterozygous missense variants lead to a significant decrease of the protease activity. ...
... Clinical and neuroimaging features of heterozygous HTRA1 stop codon carriers are quite similar to those previously reported in heterozygous missense mutation carriers. 3,6,7 Regarding extra-neurological findings, we identified 17% of patients presenting with alopecia and 39% with a spondylosis deformans, proportions quite similar with those of the meta-analysis results reported for all heterozygous HTRA1 variants in Rannikmä e et al. 5 HTRA1 is a homotrimeric enzyme and bi-allelic mutations found in CARASIL lead to a complete or almost complete loss of the enzyme activity. 2,4 Heterozygous HTRA1 missense variants were shown to behave as dominant negative mutations; the mutated allele being a loss-of-function mutant interferes with the normal function of the remaining wild-type allele, leading to a further decrease in enzyme activity. ...
Heterozygous missense HTRA1 mutations have been associated with an autosomal dominant cerebral small vessel disease whereas the pathogenicity of heterozygous HTRA1 stop codon variants is unclear. We performed a targeted high throughput sequencing of all known cerebral small vessel disease genes, including HTRA1, in 3,853 unrelated consecutive CSVD patients referred for molecular diagnosis. The frequency of heterozygous HTRA1 mutations leading to a premature stop codon in this patient cohort was compared with their frequency in large control databases. An analysis of HTRA1 messenger RNA was performed in several stop codon carrier patients. Clinical and neuroimaging features were characterized in all probands. Twenty unrelated patients carrying a heterozygous HTRA1 variant leading to a premature stop codon were identified. A highly significant difference was observed when comparing our patient cohort with control databases (gnomAD v3.1.1 (p = 3.12 x 10-17, OR = 21.9), TOPMed freeze 5 (p = 7.6 x 10-18, OR = 27.1) and 1000 Genomes (p = 1.5 x 10-5). Messenger RNA analysis performed in eight patients showed a degradation of the mutated allele strongly suggesting a haploinsufficiency. Clinical and neuroimaging features are similar to those previously reported in heterozygous missense mutation carriers, except for penetrance, which seems lower. Altogether, our findings strongly suggest that heterozygous HTRA1 stop codons are pathogenic through a haploinsufficiency mechanism. Future work will help to estimate their penetrance, an important information for genetic counseling.
... Mutated COL4A1 disrupts the basic structure of cerebral small vessels via a dominant-negative effect or haploinsufficiency, which results in autosomal-dominant cerebral small-vessel disease 1,2 . Approximately 60% of patients with COL4A1related disorders present with diffuse white matter lesions, 50% with microbleeds, and 10-30% with hemorrhagic stroke 3,4 . The high incidence of intracerebral hemorrhage illustrates the clinical differences from other hereditary cerebral small-vessel diseases, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), and hereditary endotheliopathy, retinopathy, nephropathy, and stroke (HERNS) 3 . ...
... Broad phenotypes have been linked to COL4A1-related disorders, ranging from catastrophic hemorrhage in the uterus to adult-onset hemorrhagic/ischemic stroke, epilepsy, and even clinically asymptomatic patients 4,5 . A wide intrafamilial variation in clinical symptoms has also been confirmed 11 . ...
... Cerebral hemorrhage is an important feature in COL4A1-related disorders. Perinatal cerebral hemorrhage may lead to porencephaly 1,14 , which has been observed in approximately 20% of patients 4 . Of note, the index patient presented with unilateral cerebellar hypoplasia and a cleft, Fig. 2 Brain MRI of the index patient's mother and sister and the characteristics of the glioblastoma. ...
COL4A1-related disorders are characterized by a higher incidence of cerebral hemorrhage than other hereditary cerebral small vessel diseases. Accumulating data have shown broad phenotypic variations, and extracerebral hemorrhages have been linked to these disorders. Moreover, the coexistence of neural tumors has been described. Here, we report a Japanese family with a novel COL4A1 variant, including a patient with recurrent epistaxis and glioblastoma.
... These mutations cause a broad range of phenotypes including WMH, small vessel stroke, intracerebral hemorrhage, porencephalopathy, and extracerebral manifestations (Verdura et al., 2016;Jeanne and Gould, 2017). Notably, extracerebral manifestations such as ocular and renal manifestations are a common feature in various forms of hereditary SVD (Rannikmae et al., 2020). ...
... HTRA1 mutation carriers exhibit a wide range of cerebral and extracerebral phenotypes (Rannikmae et al., 2020). To comprehensively assess disease outcomes associated with rare variants in HTRA1 or EGFL8, we performed a rare-variant burden PheWAS on standardized Phecodes in the UK Biobank. ...
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 WMH volume, the contribution of rare variants to WMH burden in the general population remains largely unexplored. We conducted a comprehensive analysis of WMH burden in the UK Biobank using publicly available whole-exome sequencing data (N=16,511) 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, beta=-0.74, se=0.13, p=9.7E-9). Applying whole-exome gene-based burden tests, we found damaging missense and loss-of-function variants in HTRA1 to associate with increased WMH volume (p=5.5E-6, FDR=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; beta=0.79, se=0.14, p=9.4E-8). The frequency of such variants in the UK Biobank population was 1 in 450. WMH volume was brought forward by approximately 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 (beta=0.26, se=0.02, p=2.9E-59) or being in the upper 99.8% percentile of the distribution of a polygenic risk score based on common genetic variants (beta=0.44, se=0.14, p=0.002). In biochemical experiments, most (6/9) of the identified protease domain variants resulted in a markedly reduced protease activity. We further found EGFL8, which showed suggestive evidence for association with WMH volume (p=1.5E-4, FDR=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 (PheWAS) 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 (OR=12.24, 95%CI [2.54-35.25], p=8.3E-5). Collectively, these findings highlight an important role of rare genetic variation and of the HTRA1 protease in determining WMH burden in the general population.
... In this article, we performed domain knowledge-lead curation of PGIs and disease-gene associations to assemble the input network. Known cSVD-associated genes summarized from a systematic review of familial cSVD were taken as seed genes [14]. We accessed the performance of representative network-based gene prioritization algorithms with cross-validation. ...
... For curation of human PGIs, three overall preferences on the nature of databases were pursued with descending priority: (i) coverage of seed genes (reviewed by Rannikmäe et al. [14]), (ii) the objectivity of database and (iii) presence of experimental evidence to support the interaction. In addition, we made sure that seed genes were covered in at least one of the databases, so that algorithms could use this prior information to prioritize other candidate genes. ...
Network-based gene prioritization algorithms are designed to prioritize disease-associated genes based on known ones using biological networks of protein interactions, gene–disease associations (GDAs) and other relationships between biological entities. Various algorithms have been developed based on different mechanisms, but it is not obvious which algorithm is optimal for a specific disease. To address this issue, we benchmarked multiple algorithms for their application in cerebral small vessel disease (cSVD). We curated protein–gene interactions (PGIs) and GDAs from databases and assembled PGI networks and disease–gene heterogeneous networks. A screening of algorithms resulted in seven representative algorithms to be benchmarked. Performance of algorithms was assessed using both leave-one-out cross-validation (LOOCV) and external validation with MEGASTROKE genome-wide association study (GWAS). We found that random walk with restart on the heterogeneous network (RWRH) showed best LOOCV performance, with median LOOCV rediscovery rank of 185.5 (out of 19 463 genes). The GenePanda algorithm had most GWAS-confirmable genes in top 200 predictions, while RWRH had best ranks for small vessel stroke-associated genes confirmed in GWAS. In conclusion, RWRH has overall better performance for application in cSVD despite its susceptibility to bias caused by degree centrality. Choice of algorithms should be determined before applying to specific disease. Current pure network-based gene prioritization algorithms are unlikely to find novel disease-associated genes that are not associated with known ones. The tools for implementing and benchmarking algorithms have been made available and can be generalized for other diseases.
