Expression quantitative trait loci-derived scores and white matter microstructure in UK Biobank: a novel approach to integrating genetics and neuroimaging

Barbu, Miruna C.; Spiliopoulou, Athina; Colombo, Marco; Clarke, Toni‐Kim; Howard, David M.; Adams, Mark J.; Shen, Xueyi; Lawrie, Stephen M.; Whalley, Heather C.

doi:10.1038/s41398-020-0724-y

Cited by 8 publications

(9 citation statements)

References 53 publications

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“…Both tracts and their connecting gray matter regions are frequently implicated in the pathophysiology of psychosis risk (see Supplementary Table 1), and facilitate wide-ranging functions, including somatosensory, attention, motor, and language processes [58,59]. While current dMRI measures are not specific to cellular/molecular mechanisms, localized FA T effects may relate to regional variability in white matter structures (e.g., myelin sheath geometry), shaped by a multitude of local cellular events and molecular signaling pathways [60,61]. These possibilities could be explored in future multimodal imaging studies that aim to deconstruct potential white matter pathologies in CHR.…”

Section: Discussionmentioning

confidence: 99%

White matter changes in psychosis risk relate to development and are not impacted by the transition to psychosis

et al. 2021

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Subtle alterations in white matter microstructure are observed in youth at clinical high risk (CHR) for psychosis. However, the timing of these changes and their relationships to the emergence of psychosis remain unclear. Here, we track the evolution of white matter abnormalities in a large, longitudinal cohort of CHR individuals comprising the North American Prodrome Longitudinal Study (NAPLS-3). Multi-shell diffusion magnetic resonance imaging data were collected across multiple timepoints (1-5 over 1 year) in 286 subjects (aged 12-32 years): 25 CHR individuals who transitioned to psychosis (CHR-P; 61 scans), 205 CHR subjects with unknown transition outcome after the 1-year follow-up period (CHR-U; 596 scans), and 56 healthy controls (195 scans). Linear mixed effects models were fitted to infer the impact of age and illness-onset on variation in the fractional anisotropy of cellular tissue (FA T ) and the volume fraction of extracellular free water (FW). Baseline measures of white matter microstructure did not differentiate between HC, CHR-U and CHR-P individuals. However, age trajectories differed between the three groups in line with a developmental effect: CHR-P and CHR-U groups displayed higher FA T in adolescence, and 4% lower FA T by 30 years of age compared to controls. Furthermore, older CHR-P subjects (20+ years) displayed 4% higher FW in the forceps major (p < 0.05). Prospective analysis in CHR-P did not reveal a significant impact of illness onset on regional FA T or FW, suggesting that transition to psychosis is not marked by dramatic change in white matter microstructure. Instead, clinical high risk for psychosisregardless of transition outcome-is characterized by subtle age-related white matter changes that occur in tandem with development.

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Section: Discussionmentioning

confidence: 99%

White matter changes in psychosis risk relate to development and are not impacted by the transition to psychosis

et al. 2021

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“…Notably, EGFL7 , a close paralogue of EGFL8 , which is likewise expressed in brain vessels, has been implicated in various vascular functions including angiogenesis and elastogenesis (Parker et al ., 2004; Lelievre et al ., 2008; Nichol and Stuhlmann, 2012). DCAKD , encoding ‘Dephospho-CoA Kinase Domain Containing protein’, is ubiquitously expressed in brain, has a putative role in neurodevelopment, and has previously been shown to be implicated in psychiatric disease (Bipolar Disorder Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2018; Barbu et al ., 2020). Moreover, studies on expression quantitative loci (eQTL) have linked expression levels of DCAKD to white matter microstructure and WMH volume (Barbu et al ., 2020; Persyn et al ., 2020).…”

Section: Discussionmentioning

confidence: 99%

“…DCAKD , encoding ‘Dephospho-CoA Kinase Domain Containing protein’, is ubiquitously expressed in brain, has a putative role in neurodevelopment, and has previously been shown to be implicated in psychiatric disease (Bipolar Disorder Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2018; Barbu et al ., 2020). Moreover, studies on expression quantitative loci (eQTL) have linked expression levels of DCAKD to white matter microstructure and WMH volume (Barbu et al ., 2020; Persyn et al ., 2020).…”

Section: Discussionmentioning

confidence: 99%

Whole-exome sequencing in 16,511 individuals reveals a role of the HTRA1 protease and its substrate EGFL8 in brain white matter hyperintensities

Malik

Beaufort

Frerich

et al. 2021

Preprint

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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.

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“…Interestingly TWAS and colocalization analyses revealed transcriptome-wide associations of WMH volume not only with NMT1, DCAKD, NT5C3B and STAT5B but also with MAPT, CRHR1 and KANSL1 21,44 , highlighting the distant cis-effect conferred by an SNP-eQTL pair. DCAKD encodes dephospho-CoA kinase domain containing protein and has a putative role in neurodevelopment 87 . NMT1 encodes N-myristoyltransferase 1, which is thought to affect astrocyte function 61 and is involved in early embryogenesis 87 .…”

Section: [H2] Mri Markers Of Covert Csvdmentioning

confidence: 99%

Genetics of common cerebral small vessel disease

et al. 2022

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Cerebral small vessel disease (cSVD) is a leading cause of ischaemic and haemorrhagic stroke and a major contributor to dementia. Covert cSVD, which is detectable with brain MRI but not manifest as clinical stroke, is highly prevalent in the general population with increasing age. Advances in technologies and collaborative work have led to substantial progress in the identification of common genetic variants that are associated with cSVD-related stroke (ischaemic and haemorrhagic) and MRI-defined covert cSVD. In this Review, we provide an overview of collaborative studies -mostly genome-wide association studies (GWAS)that have identified >50 independent genetic loci associated with the risk of cSVD. We describe how these associations have provided novel insight into the biological mechanisms involved in cSVD, revealed patterns of shared genetic variation across cSVD traits, and shed new light on the continuum between rare, monogenic and common, multifactorial cSVD. We consider how GWAS summary statistics have been leveraged for Mendelian randomization studies to explore causal pathways in cSVD and provide genetic evidence for drug effects, and how the combination of findings from GWAS with gene expression resources and drug target databases has enabled identification of putative causal genes and provided proof-of-concept for drug repositioning potential. We also discuss opportunities for polygenic risk prediction, multiancestry approaches and integration with other omics data.

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Expression quantitative trait loci-derived scores and white matter microstructure in UK Biobank: a novel approach to integrating genetics and neuroimaging

Cited by 8 publications

References 53 publications

White matter changes in psychosis risk relate to development and are not impacted by the transition to psychosis

White matter changes in psychosis risk relate to development and are not impacted by the transition to psychosis

Whole-exome sequencing in 16,511 individuals reveals a role of the HTRA1 protease and its substrate EGFL8 in brain white matter hyperintensities

Genetics of common cerebral small vessel disease

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