Aniket Mishra

• PhD in statistical genetics
• PostDoc Position at University of Bordeaux

INTRODUCTION White matter hyperintensities (WMHs), a major cerebral small vessel disease (cSVD) marker, may arise from different pathologies depending on their location. We explored clinical and genetic correlates of agnostically derived spatial WMH patterns in two longitudinal population‐based cohorts (Three‐City Study [3C]‐Dijon, LIFE‐Adult). ME...

INTRODUCTION An integrative polygenic risk score (iPRS) capturing the neurodegenerative and vascular contribution to dementia could identify high‐risk individuals and improve risk prediction. METHODS We developed an iPRS for dementia (iPRS‐DEM) in Europeans (aged 65+), comprising genetic risk for Alzheimer's disease (AD) and 23 vascular or neurode...

Peak width of skeletonized mean diffusivity (PSMD) is an emerging automated diffusion imaging marker showing clinically relevant changes in cerebral small vessel disease (cSVD), a leading cause of stroke and dementia with no mechanism-based treatment. We conducted a genome-wide association study of PSMD in 58,403 participants from 24 population-bas...

Cerebral small vessel disease (SVD) is a leading cause of strokes and a significant contributor to dementia, yet the precise mechanisms underlying its pathogenesis remain elusive. In a recent whole-exome association study involving population cohorts with SVD, we identified a variant on TRIM47 locus. The ubiquitin ligase TRIM47 is highly expressed...

Neurofilament light chain (NfL) levels in circulation have been established as a sensitive biomarker of neuro-axonal damage across a range of neurodegenerative disorders. Elucidation of the genetic architecture of blood NfL levels could provide new insights into molecular mechanisms underlying neurodegenerative disorders. In this meta-analysis of g...

INTRODUCTION: Dementia is a multifactorial disease with Alzheimer’s disease (AD) and vascular dementia (VaD) pathologies making the largest contributions. Yet, most genome-wide association studies (GWAS) focus on AD. METHODS: We conducted a GWAS of all-cause dementia (ACD) and examined the genetic overlap with VaD. Our dataset includes 800,597 indi...

INTRODUCTION: White matter hyperintensities (WMH), a major cerebral small vessel disease marker, may arise from different pathologies depending on their location. We explored clinical and genetic correlates of agnostically derived spatial WMH patterns in two longitudinal population-based cohorts (3C-Dijon, LIFE-Adult). METHODS: We derived seven WMH...

Cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia with no specific mechanism-based treatment. We used Mendelian randomization to combine a unique cerebrospinal fluid (CSF) and plasma pQTL resource with the latest European-ancestry GWAS of MRI-markers of cSVD (white matter hyperintensities, perivascular spaces). We descr...

Cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia. Genetic risk loci for white matter hyperintensities (WMH), the most common MRI-marker of cSVD in older age, were recently shown to be significantly associated with white matter (WM) microstructure on diffusion tensor imaging (signal-based) in young adults. To provide ne...

INTRODUCTION Evaluating whether genetic susceptibility modifies the impact of lifestyle‐related factors on dementia is critical for prevention. METHODS We studied 5170 participants from a French cohort of older persons free of dementia at baseline and followed for up to 17 years. The LIfestyle for BRAin health risk score (LIBRA) including 12 modif...

The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread...

Importance Vascular disease is a treatable contributor to dementia risk, but the role of specific markers remains unclear, making prevention strategies uncertain. Objective To investigate the causal association between white matter hyperintensity (WMH) burden, clinical stroke, blood pressure (BP), and dementia risk, while accounting for potential...

Background Neurofilament light chain (NfL) levels in circulation have been established as a sensitive biomarker of neuro‐axonal damage across a range of neurodegenerative disorders. Elucidation of the genetic architecture of blood NfL levels and its genetic correlation with neurological traits could therefore provide new insights into shared molecu...

Importance: There is increasing recognition that vascular disease, which can be treated, is a key contributor to dementia risk. However, the contribution of specific markers of vascular disease is unclear and, as a consequence, optimal prevention strategies remain unclear. Objective: To disentangle the causal relation of several key vascular traits...

Amyloid PET imaging has been crucial for detecting the accumulation of amyloid beta (Aβ) deposits in the brain and to study Alzheimer’s disease (AD). We performed a genome-wide association study on the largest collection of amyloid imaging data (N = 13,409) to date, across multiple ethnicities from multicenter cohorts to identify variants associate...

Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk...

Perivascular space (PVS) burden is an emerging MRI‐marker of cerebral small vessel disease (cSVD), a leading cause of stroke and dementia. Underlying mechanisms of PVS are unknown. PVS are thought to be related to the glymphatic system, involved in brain clearance of molecules such as amyloid beta. We aimed to decipher the genetic underpinnings of...

Background Cerebral white matter hyperintensities (WMH) on magnetic resonance imaging are markers of cerebral small vessel disease (cSVD), a major risk factor for Alzheimer’s disease and related dementia (ADRD). Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architectu...

Background: Neurofilament light chain (NfL) levels in circulation have been established as a sensitive biomarker of neuro-axonal damage across a range of neurodegenerative disorders. Elucidation of the genetic architecture of blood NfL levels and its genetic correlation with neurological traits could therefore provide new insights into shared molec...

Genome‐wide association studies (GWAS) have identified more than 40 genetic loci associated with Alzheimer’s disease (AD). Although vascular dementia (VaD) is the second most common type of dementia after AD, the genetic contribution to VaD is understudied. We hypothesize that common forms of dementia will share genetic risk factors. We conducted t...

Dementia is multifactorial with Alzheimer (AD) and vascular (VaD) pathologies making the largest contributions. Genome-wide association studies (GWAS) have identified over 70 genetic risk loci for AD but the genomic determinants of other dementias, including VaD remain understudied. We hypothesize that common forms of dementia will share genetic ri...

Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer’s disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, i...

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify associ...

SNPs associated with human stroke risk have been identified in the intergenic region between Forkhead family transcription factors FOXF2 and FOXQ1 , but we lack a mechanism for the association. FoxF2 is expressed in vascular mural pericytes and is important for maintaining pericyte number and stabilizing small vessels in zebrafish. The stroke-assoc...

Cerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA meth...

Cerebral small vessel disease is a leading cause of stroke and a major contributor to cognitive decline and dementia, but our understanding of specific genes underlying the cause of sporadic cerebral small vessel disease is limited. We report a genome-wide association study and a whole-exome association study on a composite extreme phenotype of cer...

Circulating total-tau levels can be used as an endophenotype to identify genetic risk factors for tauopathies and related neurological disorders. Here, we confirmed and better characterized the association of the 17q21 MAPT locus with circulating total-tau in 14,721 European participants and identified three novel loci in 953 African American parti...

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 does not manifest as clinical stroke, is highly prevalent in the general population, particularly with increasing age. Advances in technologies and collaborative work h...

Previous genome-wide association studies (GWAS) of stroke, the second leading cause of death, have been conducted in populations of predominantly European ancestry.1,2 We undertook cross-ancestry GWAS meta-analyses of stroke and its subtypes in 110,182 stroke patients (33% non-European) and 1,503,898 control individuals of five ancestries from popu...

Perivascular space burden (PVS) is an emerging and possibly the earliest magnetic resonance imaging (MRI)-marker of cerebral small vessel disease (cSVD), a leading cause of stroke and dementia. Its molecular underpinnings are unknown. Genome-wide and whole-exome association studies in 40,095 participants (21 population-based cohorts, 66.3±8.6 years...

Background Subcortical brain structures play a key role in pathological processes of age-related neurodegenerative disorders. Mounting evidence also suggests that early-life factors may have an impact on the development of common late-life neurological diseases, including genetic factors that can influence both brain maturation and neurodegeneratio...

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were...

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individua...

The size of the human head is determined by growth in the first years of life, while the rest of the body typically grows until early adulthood. Such complex developmental processes are regulated by various genes and growth pathways. Rare genetic syndromes have revealed genes that affect head size, but the genetic drivers of variation in head size...

We have carried out meta-analyses of genome-wide association studies (GWAS) (n = 23 784) of the first two principal components (PCs) that group together cortical regions with shared variance in their surface area. PC1 (global) captured variations of most regions, whereas PC2 (visual) was specific to the primary and secondary visual cortices. We ide...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Exposures to life stressors accumulate across the lifespan, with possible impact on brain health. Little is known, however, about the mechanisms mediating age-related changes in brain structure. We use a lifespan sample of participants (n = 21 251; 4-97 years) to investigate the relationship between the thickness of cerebral cortex and the expressi...

We report a composite extreme phenotype design using distribution of white matter hyperintensities and brain infarcts in a population-based cohort of older persons for gene-mapping of cerebral small vessel disease. We demonstrate its application in the 3C-Dijon whole exome sequencing (WES) study (n = 1924, nWESextremes = 512), with both single vari...

Emmanuelle Souzeau, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this Article. This has now been corrected in both the PDF and HTML versions of the Article.

Background and Purpose— Observational studies have reported increased risk of ischemic stroke among individuals with low serum 25-hydroxyvitamin D (S-25OHD) concentrations but uncertainty remains about the causality of this association. We sought to determine whether S-25OHD concentrations are causally associated with ischemic stroke and its subtyp...

Cortical thickness, surface area and volumes (MRI cortical measures) vary with age and cognitive function, and in neurological and psychiatric diseases. We examined heritability, genetic correlations and genome-wide associations of cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprised 2...

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 contr...

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene se...

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene se...

Stroke has multiple etiologies but the underlying genes and pathways are largely unknown. We conducted a multi-ancestry genome-wide association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 novel stroke risk loci bringing the total to 32. We further found shared genetic variation with related vascular tr...

p>Central corneal thickness (CCT) is one of the most heritable ocular traits and it is also a phenotypic risk factor for primary open angle glaucoma (POAG). The present study uses the BXD Recombinant Inbred (RI) strains to identify novel quantitative trait loci (QTLs) modulating CCT in the mouse with the potential of identifying a molecular link be...

We performed an exome sequence association study on extreme MRI-markers of cerebral small vessel disease (extensive-CSVD versus minimal-CSVD) in participants from the 3C-Dijon French population-based cohort study, focusing on genes harbouring causal mutations for Mendelian forms of CSVD ( NOTCH3 , HTRA1 , COL4A1 , COL4A2 , TREX1 and CTSA ). The stu...

Frontotemporal dementia (FTD) is a neurodegenerative disorder predominantly affecting the frontal and temporal lobes. Genome-wide association studies (GWAS) on FTD identified only a few risk loci. One of the possible explanations is that FTD is clinically, pathologically, and genetically heterogeneous. An important open question is to what extent e...

Genome-wide association studies in frontotemporal dementia showed limited success in identifying associated loci. This is possibly due to small sample size, allelic heterogeneity, small effect sizes of single genetic variants, and the necessity to statistically correct for testing millions of genetic variants. To overcome these issues, we performed...

The publishers regret to announce that the affiliation for the above paper was incorrectly inserted. The correct affiliation is below: Aniket Mishra ¹ , Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and the Colorectal Cancer Family Registry (CCFR), and Stuart MacGregor ¹ ¹ Statistical Genetics, QIMR Berghofer Medical Research In...

Genome-wide association studies (GWAS) have revolutionized the field of gene mapping. As the GWAS field matures, it is becoming clear that for many complex traits, a proportion of the missing heritability is attributable to common variants of individually small effect. Detecting these small effects individually can be difficult, and statistical pow...

Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increase risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic...

The cornea is the outermost layer of the eye and is a vital component of focusing incoming light on the retina. Central corneal thickness (CCT) is now recognized to have a significant role in ocular health and is a risk factor for various ocular diseases, such as keratoconus and primary open angle glaucoma. Most previous genetic studies utilized Eu...

Esophageal adenocarcinoma (EA) is a rapidly fatal cancer with rising incidence in the developed world. Most EAs arise in a metaplastic epithelium, Barrett's esophagus (BE), which is associated with greatly increased risk of EA. One of the key risk factors for both BE and EA is chronic gastroesophageal reflux disease (GERD). This study used the link...

Primary open-angle glaucoma (POAG) is a blinding disease. Two important risk factors for this disease are a positive family history and elevated intraocular pressure (IOP), which is also highly heritable. Genes found to date associated with IOP and POAG are ABCA1, CAV1/CAV2, GAS7, and TMCO1. However, these genes explain only a small part of the her...

Primary open-angle glaucoma is the most common optic neuropathy and an important cause of irreversible blindness worldwide. The optic nerve head or optic disc is divided in two parts: a central cup (without nerve fibers) surrounded by the neuroretinal rim (containing axons of the retinal ganglion cells). The International Glaucoma Genetics Consorti...

Gene-based tests such as versatile gene-based association study (VEGAS) are commonly used following per-single nucleotide polymorphism (SNP) GWAS (genome-wide association studies) analysis. Two limitations of VEGAS were that the HapMap2 reference set was used to model the correlation between SNPs and only autosomal genes were considered. HapMap2 ha...

Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 indiv...

Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 indiv...

Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for...

Corneal astigmatism is a common eye disorder characterized by irregularities in corneal curvature. Recently, the rs7677751 single nucleotide polymorphism (SNP) at the platelet-derived growth factor receptor alpha (PDGFRA) locus was found to be associated with corneal astigmatism in people of Asian ancestry. In the present study, we sought to replic...

Refractive error is the most common eye disorder worldwide and is a prominent cause of blindness. Myopia affects over 30% of Western populations and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses, including 37,382 individuals from 27 studies of European ancestry and 8,376 from 5 Asian cohorts. We identified 16 new loc...

Purpose: Irregularity in the corneal curvature (CC) is highly associated with various eye disorders such as keratoconus and myopia. The sample had limited power to find genomewide significant (5 × 10(-8)) hits but good power for replication. Thus, an attempt was made to test whether alleles in the FRAP1 and PDGFRA genes, recently found to be assoc...