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.

Background and ObjectivesTo investigate whether antemortem MRI-based atrophy subtypes of Alzheimer disease (AD) differ in neuropathologic features and comorbid non-AD pathologies at postmortem.MethodsFrom the Alzheimer's Disease Neuroimaging Initiative cohort, we included individuals with antemortem MRI evaluating brain atrophy within 2 years before death, antemortem diagnosis of AD dementia/mild cognitive impairment, and postmortem-confirmed AD neuropathologic change. Antemortem atrophy subtypes were modeled as continuous phenomena based on a recent conceptual framework: typicality (spanning limbic-predominant AD to hippocampal-sparing AD) and severity (spanning typical AD to minimal atrophy AD). Postmortem neuropathologic evaluation included AD hallmarks, β-amyloid, and tau as well as non-AD pathologies, alpha-synuclein and TAR DNA-binding protein 43 (TDP-43). We also investigated the overall concomitance across these pathologies. Partial correlations assessed the associations between antemortem atrophy subtypes and postmortem neuropathologic outcomes.ResultsIn 31 individuals (26 AD dementia/5 mild cognitive impairment, mean age = 80 years, 26% females), antemortem typicality was significantly negatively associated with neuropathologic features, including β-amyloid (rho = −0.39 overall), tau (rho = −0.38 regionally), alpha-synuclein (rho = −0.39 regionally), TDP-43 (rho = −0.49 overall), and concomitance of pathologies (rho = −0.59 regionally). Limbic-predominant AD was associated with higher Thal phase, neuritic plaque density, and presence of TDP-43 compared with hippocampal-sparing AD. Regionally, limbic-predominant AD showed a higher presence of tau and alpha-synuclein pathologies in medial temporal structures, a higher presence of TDP-43, and concomitance of pathologies subcortically/cortically compared with hippocampal-sparing AD. Antemortem severity was significantly negatively associated with concomitance of pathologies (rho = −0.43 regionally), such that typical AD showed higher concomitance of pathologies than minimal atrophy AD.DiscussionWe provide a direct antemortem-to-postmortem validation, highlighting the importance of understanding atrophy-based heterogeneity in AD relative to AD and non-AD pathologies. We suggest that (1) typicality and severity in atrophy reflect differential aspects of susceptibility of the brain to AD and non-AD pathologies; and (2) limbic-predominant AD and typical AD subtypes share similar biological pathways, making them more vulnerable to AD and non-AD pathologies compared with hippocampal-sparing AD, which may follow a different biological pathway. Our findings provide a deeper understanding of associations of atrophy subtypes in AD with different pathologies, enhancing the prevailing knowledge of biological heterogeneity in AD and could contribute toward tracking disease progression and designing clinical trials in the future.

Objective Ischemic stroke etiology remains undetermined in 30% of cases. We explored the genetic architecture of stroke classified as undetermined to test if mechanisms and risk factors underlying large‐artery atherosclerotic (LAAS), cardioembolic (CES), and small‐vessel stroke (SVS) contribute to its pathogenesis. Methods We analyzed genome‐wide data from 16,851 ischemic stroke cases and 32,473 controls. Using polygenic risk scores for LAAS, CES, and SVS, we assessed the genetic overlap with stroke of undetermined source and used pairwise genomewide association study (GWAS‐PW) to search for shared loci. We then applied Mendelian randomization (MR) to identify potentially causal risk factors of stroke of undetermined source. Results Genetic risk for LAS, CES, and SVS was associated with stroke of undetermined source pointing to overlap in their genetic architecture. Pairwise analyses revealed 19 shared loci with LAAS, 2 with CES, and 5 with SVS that have been implicated in atherosclerosis‐related phenotypes. Genetic liability to both carotid atherosclerosis and atrial fibrillation was associated with stroke of undetermined source, but the association with atrial fibrillation was attenuated after excluding cases with incomplete diagnostic workup. MR analyses showed effects of genetically determinants of blood pressure, diabetes, waist‐to‐hip ratio, inflammatory pathways (IL‐6 signaling, MCP‐1/CCL2 levels), and factor XI levels on stroke of undetermined source. Interpretation Stroke of undetermined source shares genetic and vascular risk factors with other stroke subtypes, especially LAAS, thus highlighting the diagnostic limitations of current subtyping approaches. The potentially causal associations with carotid atherosclerosis and atherosclerotic risk factors might have implications for prevention strategies targeting these mechanisms. ANN NEUROL 2022;91:640–651

Background and Purpose: Observational studies suggest an association of stroke with cardiac traits beyond atrial fibrillation, the leading source of cardioembolism. However, controversy remains regarding a causal role of these traits in stroke pathogenesis. Here, we leveraged genetic data to systematically assess associations between cardiac traits and stroke risk using a Mendelian Randomization framework. Methods: We studied 66 cardiac traits including cardiovascular diseases, magnetic resonance imaging–derived cardiac imaging, echocardiographic imaging, and electrocardiographic measures, as well as blood biomarkers in a 2-sample Mendelian Randomization approach. Genetic predisposition to each trait was explored for associations with risk of stroke and stroke subtypes in data from the MEGASTROKE consortium (40 585 cases/406 111 controls). Using multivariable Mendelian Randomization, we adjusted for potential pleiotropic or mediating effects relating to atrial fibrillation, coronary artery disease, and systolic blood pressure. Results: As expected, we observed strong independent associations between genetic predisposition to atrial fibrillation and cardioembolic stroke and between genetic predisposition to coronary artery disease as a proxy for atherosclerosis and large-artery stroke. Our data-driven analyses further indicated associations of genetic predisposition to both heart failure and lower resting heart rate with stroke. However, these associations were explained by atrial fibrillation, coronary artery disease, and systolic blood pressure in multivariable analyses. Genetically predicted P-wave terminal force in V1, an electrocardiographic marker for atrial cardiopathy, was inversely associated with large-artery stroke. Conclusions: Available genetic data do not support substantial effects of cardiac traits on the risk of stroke beyond known clinical risk factors. Our findings highlight the need to carefully control for confounding and other potential biases in studies examining candidate cardiac risk factors for stroke.