Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes.

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aß42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.

Diffusion imaging genomics provides novel insight into early mechanisms of cerebral small vessel disease.

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 new insights into these early changes in WM microstructure and their relation with cSVD, we sought to explore the genetic underpinnings of cutting-edge tissue-based diffusion imaging markers across the adult lifespan. We conducted a genome-wide association study of neurite orientation dispersion and density imaging (NODDI) markers in young adults (i-Share study: N = 1 758, (mean[range]) 22.1[18-35] years), with follow-up in young middle-aged (Rhineland Study: N = 714, 35.2[30-40] years) and late middle-aged to older individuals (UK Biobank: N = 33 224, 64.3[45-82] years). We identified 21 loci associated with NODDI markers across brain regions in young adults. The most robust association, replicated in both follow-up cohorts, was with Neurite Density Index (NDI) at chr5q14.3, a known WMH locus in VCAN. Two additional loci were replicated in UK Biobank, at chr17q21.2 with NDI, and chr19q13.12 with Orientation Dispersion Index (ODI). Transcriptome-wide association studies showed associations of STAT3 expression in arterial and adipose tissue (chr17q21.2) with NDI, and of several genes at chr19q13.12 with ODI. Genetic susceptibility to larger WMH volume, but not to vascular risk factors, was significantly associated with decreased NDI in young adults, especially in regions known to harbor WMH in older age. Individually, seven of 25 known WMH risk loci were associated with NDI in young adults. In conclusion, we identified multiple novel genetic risk loci associated with NODDI markers, particularly NDI, in early adulthood. These point to possible early-life mechanisms underlying cSVD and to processes involving remyelination, neurodevelopment and neurodegeneration, with a potential for novel approaches to prevention.

Stroke-associated intergenic variants modulate a human FOXF2 transcriptional enhancer.

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-associated SNPs are located in a previously unknown transcriptional enhancer for FOXF2, functional in human cells and zebrafish. We identify critical enhancer regions for FOXF2 gene expression, including binding sites occupied by transcription factors ETS1, RBPJ, and CTCF. rs74564934, a stroke-associated SNP adjacent to the ETS1 binding site, decreases enhancer function, as does mutation of RPBJ sites. rs74564934 is significantly associated with the increased risk of any stroke, ischemic stroke, small vessel stroke, and elevated white matter hyperintensity burden in humans. Foxf2 has a conserved function cross-species and is expressed in vascular mural pericytes of the vessel wall. Thus, stroke-associated SNPs modulate enhancer activity and expression of a regulator of vascular stabilization, FOXF2, thereby modulating stroke risk.

Early detection of white matter hyperintensities using SHIVA-WMH detector.

White matter hyperintensities (WMHs) are well-established markers of cerebral small vessel disease, and are associated with an increased risk of stroke, dementia, and mortality. Although their prevalence increases with age, small and punctate WMHs have been reported with surprisingly high frequency even in young, neurologically asymptomatic adults. However, most automated methods to segment WMH published to date are not optimized for detecting small and sparse WMH. Here we present the SHIVA-WMH tool, a deep-learning (DL)-based automatic WMH segmentation tool that has been trained with manual segmentations of WMH in a wide range of WMH severity. We show that it is able to detect WMH with high efficiency in subjects with only small punctate WMH as well as in subjects with large WMHs (i.e., with confluency) in evaluation datasets from three distinct databases: magnetic resonance imaging-Share consisting of young university students, MICCAI 2017 WMH challenge dataset consisting of older patients from memory clinics, and UK Biobank with community-dwelling middle-aged and older adults. Across these three cohorts with a wide-ranging WMH load, our tool achieved voxel-level and individual lesion cluster-level Dice scores of 0.66 and 0.71, respectively, which were higher than for three reference tools tested: the lesion prediction algorithm implemented in the lesion segmentation toolbox (LPA: Schmidt), PGS tool, a DL-based algorithm and the current winner of the MICCAI 2017 WMH challenge (Park et al.), and HyperMapper tool (Mojiri Forooshani et al.), another DL-based method with high reported performance in subjects with mild WMH burden. Our tool is publicly and openly available to the research community to facilitate investigations of WMH across a wide range of severity in other cohorts, and to contribute to our understanding of the emergence and progression of WMH.

Prevalence of Mutations in Mendelian Stroke Genes in Early Onset Stroke Patients.

OBJECTIVE: Heritability of stroke is assumed not to be low, especially in the young stroke population. However, most genetic studies have been performed in highly selected patients with typical clinical or neuroimaging characteristics. We investigated the prevalence of 15 Mendelian stroke genes and explored the relationships between variants and the clinical and neuroimaging characteristics in a large, unselected, young stroke population. METHODS: We enrolled patients aged ≤55 years with stroke or transient ischemic attack from a prospective, nationwide, multicenter stroke registry. We identified clinically relevant genetic variants (CRGVs) in 15 Mendelian stroke genes (GLA, NOTCH3, HTRA1, RNF213, ACVRL1, ENG, CBS, TREX1, ABCC6, COL4A1, FBN1, NF1, COL3A1, MT-TL1, and APP) using a customized, targeted next generation sequencing panel. RESULTS: Among 1,033 patients, 131 (12.7%) had 28 CRGVs, most frequently in RNF213 (n = 59), followed by ABCC6 (n = 53) and NOTCH3 (n = 15). The frequency of CRGVs differed by ischemic stroke subtypes (p < 0.01): the highest in other determined etiology (20.1%), followed by large artery atherosclerosis (13.6%). It also differed between patients aged ≤35 years and those aged 51 to 55 years (17.1% vs 9.3%, p = 0.02). Only 27.1% and 26.7% of patients with RNF213 and NOTCH3 variants had typical neuroimaging features of the corresponding disorders, respectively. Variants of uncertain significance (VUSs) were found in 15.4% patients. INTERPRETATION: CRGVs in 15 Mendelian stroke genes may not be uncommon in the young stroke population. The majority of patients with CRGVs did not have typical features of the corresponding monogenic disorders. Clinical implications of having CRGVs or VUSs should be explored. ANN NEUROL 2023;93:768-782.

Stroke Genetics: Discovery, Insight Into Mechanisms, and Clinical Perspectives.

Stroke is the second leading cause of death worldwide and a complex, heterogeneous condition. In this review, we provide an overview of the current knowledge on monogenic and multifactorial forms of stroke, highlighting recent insight into the continuum between these. We describe how, in recent years, large-scale genome-wide association studies have enabled major progress in deciphering the genetic basis for stroke and its subtypes, although more research is needed to interpret these findings. We cover the potential of stroke genetics to reveal novel pathophysiological processes underlying stroke, to accelerate the discovery of new therapeutic approaches, and to identify individuals in the population who are at high risk of stroke and could be targeted for tailored preventative interventions.

Habitual coffee consumption and risk of dementia in older persons: modulation by CYP1A2 polymorphism.

Higher coffee consumption has been associated with reduced dementia risk, yet with inconsistencies across studies. CYP1A2 polymorphisms, which affects caffeine metabolism, may modulate the association between coffee and the risk of dementia and Alzheimer's disease (AD). We included 5964 participants of the Three-City Study (mean age 74 years-old), free of dementia at baseline when they reported their daily coffee consumption, with available genome-wide genotyping and followed for dementia over a median of 9.0 (range 0.8-18.7) years. In Cox proportional-hazards models, the relationship between coffee consumption and dementia risk was modified by CYP1A2 polymorphism at rs762551 (p for interaction = 0.034). In multivariable-adjusted models, coffee intake was linearly associated with a decreased risk of dementia among carriers of the C allele only ("slower caffeine metabolizers"; HR for 1-cup increased [95% CI] 0.90 [0.83-0.97]), while in non-carriers ("faster caffeine metabolizers"), there was no significant association but a J-shaped trend toward a decrease in dementia risk up to 3 cups/day and increased risk beyond. Thus, compared to null intake, drinking ≥ 4 cups of coffee daily was associated with a reduced dementia risk in slower but not faster metabolizers (HR [95% CI] for ≥ 4 vs. 0 cup/day = 0.45 [0.25-0.80] and 1.32 [0.89-1.96], respectively). Results were similar when studying AD and another CYP1A2 candidate polymorphism (rs2472304), but no interaction was found with CYP1A2 rs2472297 or rs2470893. In this cohort, a linear association of coffee intake to lower dementia risk was apparent only among carriers of CYP1A2 polymorphisms predisposing to slower caffeine metabolism.

Association of LIfestyle for BRAin health risk score (LIBRA) and genetic susceptibility with incident dementia and cognitive decline.

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 modifiable factors was constructed at baseline (higher score indicating greater risk) and was related to both subsequent cognitive decline and dementia incidence, according to genetic susceptibility to dementia (reflected by the apolipoprotein E [APOE] ε4 allele and a genetic risk score [GRS]). RESULTS: The LIBRA was associated with higher dementia incidence, with no significant effect modification by genetics (hazard ratio for one point score = 1.09 [95% confidence interval, 1.05; 1.13]) in APOE ε4 non-carriers and = 1.15 [1.08; 1.22] in carriers; P = 0.15 for interaction). Similar findings were obtained with the GRS and with cognitive decline. DISCUSSION: Lifestyle-based prevention may be effective whatever the genetic susceptibility to dementia.

Circulating Metabolome and White Matter Hyperintensities in Women and Men.

BACKGROUND: White matter hyperintensities (WMH), identified on T2-weighted magnetic resonance images of the human brain as areas of enhanced brightness, are a major risk factor of stroke, dementia, and death. There are no large-scale studies testing associations between WMH and circulating metabolites. METHODS: We studied up to 9290 individuals (50.7% female, average age 61 years) from 15 populations of 8 community-based cohorts. WMH volume was quantified from T2-weighted or fluid-attenuated inversion recovery images or as hypointensities on T1-weighted images. Circulating metabolomic measures were assessed with mass spectrometry and nuclear magnetic resonance spectroscopy. Associations between WMH and metabolomic measures were tested by fitting linear regression models in the pooled sample and in sex-stratified and statin treatment-stratified subsamples. Our basic models were adjusted for age, sex, age×sex, and technical covariates, and our fully adjusted models were also adjusted for statin treatment, hypertension, type 2 diabetes, smoking, body mass index, and estimated glomerular filtration rate. Population-specific results were meta-analyzed using the fixed-effect inverse variance-weighted method. Associations with false discovery rate (FDR)-adjusted P values (PFDR)<0.05 were considered significant. RESULTS: In the meta-analysis of results from the basic models, we identified 30 metabolomic measures associated with WMH (PFDR<0.05), 7 of which remained significant in the fully adjusted models. The most significant association was with higher level of hydroxyphenylpyruvate in men (PFDR.full.adj=1.40×10-7) and in both the pooled sample (PFDR.full.adj=1.66×10-4) and statin-untreated (PFDR.full.adj=1.65×10-6) subsample. In men, hydroxyphenylpyruvate explained 3% to 14% of variance in WMH. In men and the pooled sample, WMH were also associated with lower levels of lysophosphatidylcholines and hydroxysphingomyelins and a larger diameter of low-density lipoprotein particles, likely arising from higher triglyceride to total lipids and lower cholesteryl ester to total lipids ratios within these particles. In women, the only significant association was with higher level of glucuronate (PFDR=0.047). CONCLUSIONS: Circulating metabolomic measures, including multiple lipid measures (eg, lysophosphatidylcholines, hydroxysphingomyelins, low-density lipoprotein size and composition) and nonlipid metabolites (eg, hydroxyphenylpyruvate, glucuronate), associate with WMH in a general population of middle-aged and older adults. Some metabolomic measures show marked sex specificities and explain a sizable proportion of WMH variance.

Causal Effect of the 25-Hydroxyvitamin D Concentration on Cerebral Small Vessel Disease: A Mendelian Randomization Study.

BACKGROUND: Previous observational studies reported that a lower serum 25-hydroxyvitamin D [25(OH)D] concentration is associated with a higher burden of cerebral small vessel disease (cSVD). The causality of this association is uncertain, but it would be clinically important, given that 25(OH)D can be a target for intervention. We tried to examine the causal effect of 25(OH)D concentration on cSVD-related phenotypes using a Mendelian randomization approach. METHODS: Genetic instruments for each serum 25(OH)D concentration and cSVD-related phenotypes (lacunar stroke, white matter hyperintensity, cerebral microbleeds, and perivascular spaces) were derived from large-scale genome-wide association studies. We performed 2-sample Mendelian randomization analyses with multiple post hoc sensitivity analyses. A bidirectional Mendelian randomization approach was also used to explore the possibility of reverse causation. RESULTS: We failed to find any significant causal effect of 25(OH)D concentration on cSVD-related phenotypes (odds ratio [95% CI], 1.00 [0.87-1.16], 1.01 [0.96-1.07], 1.06 [0.85-1.33], 1.00 [0.97-1.03], 1.02 [0.99-1.04], 1.01 [0.99-1.04] for lacunar stroke, white matter hyperintensity, cerebral microbleeds, and white matter, basal ganglia, hippocampal perivascular spaces, respectively). These results were reproduced in the sensitivity analyses accounting for genetic pleiotropy. Conversely, when we examined the effects of cSVD phenotypes on 25(OH)D concentration, cerebral microbleeds were negatively associated with 25(OH)D concentration (0.94 [0.92-0.96]). CONCLUSIONS: Given the adequate statistical power (>0.8) of the analyses, our findings suggest that the previously reported association between 25(OH)D concentration and cSVD phenotypes might not be causal and partly attributed to reverse causation.

Genetic Risk Score for Intracranial Aneurysms: Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity.

BACKGROUND: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. METHODS: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. RESULTS: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20-1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01-1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59-0.67) to 0.65 (95% CI, 0.62-0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (ß=-4.82×10-3 per year [95% CI, -6.49×10-3 to -3.14×10-3]; P=1.82×10-8), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86-0.98]; P=0.0041). CONCLUSIONS: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.

Association between ABO haplotypes and the risk of venous thrombosis: impact on disease risk estimation.

Genetic risk score (GRS) analysis is a popular approach to derive individual risk prediction models for complex diseases. In venous thrombosis (VT), such type of analysis shall integrate information at the ABO blood group locus, which is one of the major susceptibility loci. However, there is no consensus about which single nucleotide polymorphisms (SNPs) must be investigated when properly assessing association between ABO locus and VT risk. Using comprehensive haplotype analyses of ABO blood group tagging SNPs in 5425 cases and 8445 controls from 6 studies, we demonstrate that using only rs8176719 (tagging O1) to correctly assess the impact of ABO locus on VT risk is suboptimal, because 5% of rs8176719-delG carriers do not have an increased risk of developing VT. Instead, we recommend the use of 4 SNPs, rs2519093 (tagging A1), rs1053878 (A2), rs8176743 (B), and rs41302905 (O2), when assessing the impact of ABO locus on VT risk to avoid any risk misestimation. Compared with the O1 haplotype, the A2 haplotype is associated with a modest increase in VT risk (odds ratio, âˆ¼1.2), the A1 and B haplotypes are associated with an âˆ¼1.8-fold increased risk, whereas the O2 haplotype tends to be slightly protective (odds ratio, âˆ¼0.80). In addition, although the A1 and B blood groups are associated with increased von Willebrand factor and factor VIII plasma levels, only the A1 blood group is associated with ICAM levels, but in an opposite direction, leaving additional avenues to be explored to fully understand the spectrum of biological effects mediated by ABO locus on cardiovascular traits.

PHACTR-1 (Phosphatase and Actin Regulator 1) Deficiency in Either Endothelial or Smooth Muscle Cells Does Not Predispose Mice to Nonatherosclerotic Arteriopathies in 3 Transgenic Mice.

BACKGROUND: Genome-wide association studies have revealed robust associations of common genetic polymorphisms in an intron of the PHACTR-1 (phosphatase and actin regulator 1) gene (chr6p24), with cervical artery dissection, spontaneous coronary artery dissection, and fibromuscular dysplasia. The aim was to assess its role in the pathogenesis of cervical artery dissection or fibromuscular dysplasia. METHODS: Using various tissue-specific Cre-driver mouse lines, Phactr1 was deleted either in endothelial cells using 2 tissue-specific Cre-driver (PDGFB [platelet-derived growth factor B]-CreERT2 mice and Tie2 [tyrosine kinase with immunoglobulin and EGF homology domains]-Cre) and smooth muscle cells (smooth muscle actin-CreERT2) with a third tissue-specific Cre-driver. RESULTS: To test the efficacy of the Phactr1 deletion after cre-induction, we confirmed first, a decrease in Phactr1 transcription and Phactr1 expression in endothelial cell and smooth muscle cell isolated from Phactr1iPDGFB and Phactr1iSMA mice. Irrespective to the tissue or the duration of the deletion, mice did not spontaneously display pathological phenotype or vascular impairment: mouse survival, growth, blood pressure, large vessel morphology, or actin organization were not different in knockout mice than their comparatives littermates. Challenging vascular function and repair either by angiotensin II-induced hypertension or limb ischemia did not lead to vascular morphology or function impairment in Phactr1-deleted mice. Similarly, there were no more consequences of Phactr1 deletion during embryogenesis in endothelial cells. CONCLUSIONS: Loss of PHACTR-1 function in the cells involved in vascular physiology does not appear to induce a pathological vascular phenotype. The in vivo effect of the intronic variation described in genome-wide association studies is unlikely to involve downregulation in PHACTR-1 expression.

Genome-wide association study reveals novel genetic loci: a new polygenic risk score for mitral valve prolapse.

AIMS: Mitral valve prolapse (MVP) is a common valvular heart disease with a prevalence of >2% in the general adult population. Despite this high incidence, there is a limited understanding of the molecular mechanism of this disease, and no medical therapy is available for this disease. We aimed to elucidate the genetic basis of MVP in order to better understand this complex disorder. METHODS AND RESULTS: We performed a meta-analysis of six genome-wide association studies that included 4884 cases and 434 649 controls. We identified 14 loci associated with MVP in our primary analysis and 2 additional loci associated with a subset of the samples that additionally underwent mitral valve surgery. Integration of epigenetic, transcriptional, and proteomic data identified candidate MVP genes including LMCD1, SPTBN1, LTBP2, TGFB2, NMB, and ALPK3. We created a polygenic risk score (PRS) for MVP and showed an improved MVP risk prediction beyond age, sex, and clinical risk factors. CONCLUSION: We identified 14 genetic loci that are associated with MVP. Multiple analyses identified candidate genes including two transforming growth factor-ß signalling molecules and spectrin ß. We present the first PRS for MVP that could eventually aid risk stratification of patients for MVP screening in a clinical setting. These findings advance our understanding of this common valvular heart disease and may reveal novel therapeutic targets for intervention.

Genome-Wide Association Study Identifies First Locus Associated with Susceptibility to Cerebral Venous Thrombosis.

OBJECTIVE: Cerebral venous thrombosis (CVT) is an uncommon form of stroke affecting mostly young individuals. Although genetic factors are thought to play a role in this cerebrovascular condition, its genetic etiology is not well understood. METHODS: A genome-wide association study was performed to identify genetic variants influencing susceptibility to CVT. A 2-stage genome-wide study was undertaken in 882 Europeans diagnosed with CVT and 1,205 ethnicity-matched control subjects divided into discovery and independent replication datasets. RESULTS: In the overall case-control cohort, we identified highly significant associations with 37 single nucleotide polymorphisms (SNPs) within the 9q34.2 region. The strongest association was with rs8176645 (combined p = 9.15 × 10-24 ; odds ratio [OR] = 2.01, 95% confidence interval [CI] = 1.76-2.31). The discovery set findings were validated across an independent European cohort. Genetic risk score for this 9q34.2 region increases CVT risk by a pooled estimate OR = 2.65 (95% CI = 2.21-3.20, p = 2.00 × 10-16 ). SNPs within this region were in strong linkage disequilibrium (LD) with coding regions of the ABO gene. The ABO blood group was determined using allele combination of SNPs rs8176746 and rs8176645. Blood groups A, B, or AB, were at 2.85 times (95% CI = 2.32-3.52, p = 2.00 × 10-16 ) increased risk of CVT compared with individuals with blood group O. INTERPRETATION: We present the first chromosomal region to robustly associate with a genetic susceptibility to CVT. This region more than doubles the likelihood of CVT, a risk greater than any previously identified thrombophilia genetic risk marker. That the identified variant is in strong LD with the coding region of the ABO gene with differences in blood group prevalence provides important new insights into the pathophysiology of CVT. ANN NEUROL 2021;90:777-788.

A Mendelian randomization of γ' and total fibrinogen levels in relation to venous thromboembolism and ischemic stroke.

Fibrinogen is a key component of the coagulation cascade, and variation in its circulating levels may contribute to thrombotic diseases, such as venous thromboembolism (VTE) and ischemic stroke. Gamma prime (γ') fibrinogen is an isoform of fibrinogen that has anticoagulant properties. We applied 2-sample Mendelian randomization (MR) to estimate the causal effect of total circulating fibrinogen and its isoform, γ' fibrinogen, on risk of VTE and ischemic stroke subtypes using summary statistics from genome-wide association studies. Genetic instruments for γ' fibrinogen and total fibrinogen were selected, and the inverse-variance weighted MR approach was used to estimate causal effects in the main analysis, complemented by sensitivity analyses that are more robust to the inclusion of pleiotropic variants, including MR-Egger, weighted median MR, and weighted mode MR. The main inverse-variance weighted MR estimates based on a combination of 16 genetic instruments for γ' fibrinogen and 75 genetic instruments for total fibrinogen indicated a protective effect of higher γ' fibrinogen and higher total fibrinogen on VTE risk. There was also a protective effect of higher γ' fibrinogen levels on cardioembolic and large artery stroke risk. Effect estimates were consistent across sensitivity analyses. Our results provide evidence to support effects of genetically determined γ' fibrinogen on VTE and ischemic stroke risk. Further research is needed to explore mechanisms underlying these effects and their clinical applications.

Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers.

Amyloid-beta 42 (Aß42) 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, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aß42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aß42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.

Stroke Genetics: Turning Discoveries into Clinical Applications.

The field of medical and population genetics in stroke is moving at a rapid pace and has led to unanticipated opportunities for discovery and clinical applications. Genome-wide association studies have highlighted the role of specific pathways relevant to etiologically defined subtypes of stroke and to stroke as a whole. They have further offered starting points for the exploration of novel pathways and pharmacological strategies in experimental systems. Mendelian randomization studies continue to provide insights in the causal relationships between exposures and outcomes and have become a useful tool for predicting the efficacy and side effects of drugs. Additional applications that have emerged from recent discoveries include risk prediction based on polygenic risk scores and pharmacogenomics. Among the topics currently moving into focus is the genetics of stroke outcome. While still at its infancy, this field is expected to boost the development of neuroprotective agents. We provide a brief overview on recent progress in these areas.

Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation.

The Alzheimer's Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10-7), an immunoglobulin gene whose antibodies interact with ß-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10-7), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10-6). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.

Correction: Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation.

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