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BACKGROUND As global populations age and become susceptible to neurodegenerative illnesses, new therapies for Alzheimer’s Disease (AD) are urgently needed. Existing data resources for drug discovery and repurposing fail to capture heterogeneous biomedical knowledge that is central to the disease’s etiology and response to drugs. We designed the Alzheimer’s Knowledge Base (AlzKB) to alleviate this need by providing a comprehensive knowledge representation of AD etiology and candidate therapeutics. OBJECTIVE We designed the Alzheimer’s Knowledge Base (AlzKB) to alleviate this need by providing a comprehensive knowledge representation of AD etiology and candidate therapeutics. METHODS We designed AlzKB as a large, heterogeneous graph knowledge base assembled using 22 diverse external data sources describing biological and pharmaceutical entities at different levels of organization (chemicals, genes, anatomy, diseases, etc.). AlzKB uses an OWL 2 ontology to enforce semantic consistency and allow for ontological inference. We provide a public version of AlzKB and allow users to run and modify local versions of the knowledge base. RESULTS AlzKB is freely available at http://alzkb.ai, and currently contains 118,902 entities with 1,309,527 relationships between those entities. To demonstrate its value, we use graph data science and machine learning to (a.) propose new therapeutic targets based on similarities of AD to Parkinson Disease and (b.) repurpose existing drugs that may treat AD. For each use case, AlzKB recovers known therapeutic associations while proposing biologically plausible new ones. CONCLUSIONS AlzKB is a new, publicly available knowledge resource that enables researchers to discover complex translational associations for AD drug discovery. Through two use-cases, we show that it is a valuable tool for proposing novel therapeutic hypotheses based on public biomedical knowledge.

Human genomic diversity has been shaped by both ancient and ongoing challenges from viruses. The current coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a devastating impact on population health. However, genetic diversity and evolutionary forces impacting host genes related to SARS-CoV-2 infection are not well understood. We investigated global patterns of genetic variation and signatures of natural selection at host genes relevant to SARS-CoV-2 infection (angiotensin converting enzyme 2 [ACE2], transmembrane protease serine 2 [TMPRSS2], dipeptidyl peptidase 4 [DPP4], and lymphocyte antigen 6 complex locus E [LY6E]). We analyzed data from 2,012 ethnically diverse Africans and 15,977 individuals of European and African ancestry with electronic health records and integrated with global data from the 1000 Genomes Project. At ACE2, we identified 41 nonsynonymous variants that were rare in most populations, several of which impact protein function. However, three nonsynonymous variants (rs138390800, rs147311723, and rs145437639) were common among central African hunter-gatherers from Cameroon (minor allele frequency 0.083 to 0.164) and are on haplotypes that exhibit signatures of positive selection. We identify signatures of selection impacting variation at regulatory regions influencing ACE2 expression in multiple African populations. At TMPRSS2, we identified 13 amino acid changes that are adaptive and specific to the human lineage compared with the chimpanzee genome. Genetic variants that are targets of natural selection are associated with clinical phenotypes common in patients with COVID-19. Our study provides insights into global variation at host genes related to SARS-CoV-2 infection, which have been shaped by natural selection in some populations, possibly due to prior viral infections.

Normal and pathologic neurobiological processes influence brain morphology in coordinated ways that give rise to structural covariance patterns across brain regions and individuals. We present a mega-analysis of structural covariance with magnetic resonance imaging of 50,699 healthy and diseased individuals (12 studies, 130 sites, and 12 countries) over their lifespan (ages 5 through 97). Patterns of structural covariance (PSC) were highly heritable (0.05< h2 -log10[p-value] > 8.8): 1245 previously unreported, and 69% of them independently replicated (-log10[p-value] = 4.5). Associations revealed an imaging phenotypic landscape between 2003 PSCs and 49 clinical and cognitive traits at multiple scales. We constructed machine learning-derived individualized imaging signatures for various disease diagnoses using PSC features at multiple scales, suggesting that disease effects on the brain were better manifested in a multi-scale continuum than on any single scale. Experimental results were integrated into the Multi-scale Structural Imaging Covariance (MuSIC) atlas and made publicly accessible through the BRIDGEPORT web portal (https://www.cbica.upenn.edu/bridgeport/). Our results reveal strong associations between brain structural covariance, genetics, and clinical phenotypes, supporting that PSCs can serve as an endophenotypic anatomic dictionary in future research.

Cardiometabolic diseases are highly comorbid, but their relationship with female-specific health conditions (breast cancer, endometriosis, pregnancy complications) is understudied. Using electronic health record data from 71,008 ancestrally diverse females, we examined relationships between 23 obstetrical/gynecological conditions and 4 cardiometabolic phenotypes (body mass index [BMI], coronary artery disease [CAD], type 2 diabetes [T2D], and hypertension) using cross-trait genetic correlation analyses, polygenic risk scores (PRSs), Mendelian randomization (MR), and chronology analyses. We observed 29 significant associations between cardiometabolic PRSs and obstetrical/gynecological conditions (BMI and endometrial cancer; BMI and polycystic ovarian syndrome [PCOS)]; T2D and gestational diabetes; T2D and PCOS). MR analysis provided additional evidence of independent causal effects. We also identified an inverse association between CAD and breast cancer. High cardiometabolic PRSs were associated with early development of PCOS and gestational hypertension. We conclude that polygenic susceptibility to cardiometabolic traits is associated with elevated risk of certain female-specific health conditions.

Supplemental Digital Content is available in the text., Background: Abdominal aortic aneurysm (AAA) is an important cause of cardiovascular mortality; however, its genetic determinants remain incompletely defined. In total, 10 previously identified risk loci explain a small fraction of AAA heritability. Methods: We performed a genome-wide association study in the Million Veteran Program testing ≈18 million DNA sequence variants with AAA (7642 cases and 172 172 controls) in veterans of European ancestry with independent replication in up to 4972 cases and 99 858 controls. We then used mendelian randomization to examine the causal effects of blood pressure on AAA. We examined the association of AAA risk variants with aneurysms in the lower extremity, cerebral, and iliac arterial beds, and derived a genome-wide polygenic risk score (PRS) to identify a subset of the population at greater risk for disease. Results: Through a genome-wide association study, we identified 14 novel loci, bringing the total number of known significant AAA loci to 24. In our mendelian randomization analysis, we demonstrate that a genetic increase of 10 mm Hg in diastolic blood pressure (odds ratio, 1.43 [95% CI, 1.24–1.66]; P=1.6×10−6), as opposed to systolic blood pressure (odds ratio, 1.06 [95% CI, 0.97–1.15]; P=0.2), likely has a causal relationship with AAA development. We observed that 19 of 24 AAA risk variants associate with aneurysms in at least 1 other vascular territory. A 29-variant PRS was strongly associated with AAA (odds ratioPRS, 1.26 [95% CI, 1.18–1.36]; PPRS=2.7×10−11 per SD increase in PRS), independent of family history and smoking risk factors (odds ratioPRS+family history+smoking, 1.24 [95% CI, 1.14–1.35]; PPRS=1.27×10−6). Using this PRS, we identified a subset of the population with AAA prevalence greater than that observed in screening trials informing current guidelines. Conclusions: We identify novel AAA genetic associations with therapeutic implications and identify a subset of the population at significantly increased genetic risk of AAA independent of family history. Our data suggest that extending current screening guidelines to include testing to identify those with high polygenic AAA risk, once the cost of genotyping becomes comparable with that of screening ultrasound, would significantly increase the yield of current screening at reasonable cost.

Introduction & Purpose: Breast density, the relative amount of fibroglandular versus fatty tissue in the breast, is one of the strongest breast cancer risk factors. Understanding genetic factors associated with breast density may help clarify mechanisms by which breast density increases breast cancer risk. To date, 46 genetic loci have been associated with breast density, however, these studies have been performed among predominantly European ancestry populations. This study sought to identify genetic factors associated with breast density among women of African ancestry. Methods: We utilized a cohort of women aged 40-85 years who underwent screening mammography at the Hospital of the University of Pennsylvania from 2010-2014. The cohort was linked to the Penn Medicine BioBank (PMBB), a repository of DNA samples from consenting patients. We conducted a genome-wide association study (GWAS) of breast density among women with available genotypes who either self-reported their race as Black/African American, or had an African ancestry genotype (N = 1,323). For each mammogram, the publicly available “LIBRA” software (v1.0.4) was used to quantify dense area and area percent density (dense area divided by breast area) from raw (i.e., FOR PROCESSING) full-field digital mammograms (Selenia Dimensions, Hologic Inc.). Women completed a breast cancer risk factor questionnaire at the time of mammography and BMI was obtained from electronic health records. We tested for associations of dense area and area percent density with ~8.5M common variants, adjusting for age, BMI, menopausal status, and two principle components of ancestry as covariates. Results: We identified three novel loci associated with dense area at genome wide significance (p < 5e-08), including KCNA3 (rs61803939, p =3.40e-08, beta=3.26, SE=0.59) and two nearby loci on chromosome 19, ZNF486 (rs6511094, p =1.41e-08, beta=2.44, SE=0.43) and LOC100129265 (rs1428621382 p = 5.13E-08, beta=2.40, SE=0.44). Our results also replicated three previously reported signals near genes TET3 associated with dense area, TNS1 and SMIM25 associated with area percent density at nominally significant p < 1e-06. Conclusions: To our knowledge, this is the first breast density GWAS in women of African ancestry. Although the study had a small sample size, the analyses replicated associations of three known genes and also identified three novel breast density loci. Notably, variant rs61803939 mapping to KCNA3 gene is present in samples of African ancestry at a higher frequency (MAF=0.14) than in samples of European ancestry (MAF=0.09). Additionally, this variant also has a high oncogenecity score (Phred Score=21.9) and is estimated as likely driver of cancer. Further investigation of the role of variants in KCNA3 in breast density and in influencing the breast cancer risk are warranted, as are larger GWAS evaluating genetic variants for breast density among African ancestry populations. Citation Format: Shefali Verma, Lindsay Guare, Aimilia Gastounioti, Sarah Ehsan, Emily F. Conant, Marylyn Ritchie, Despina Kontos, Anne Marie McCarthy. Genome wide association study of breast density among women of African ancestry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5871.

While newborns and children with hearing loss are routinely offered genetic testing, adults are rarely clinically tested for a genetic etiology. One clinically actionable result from genetic testing in children is the discovery of variants in syndromic hearing loss genes. EYA4 is a known hearing loss gene which is also involved in important pathways in cardiac tissue. The pleiotropic effects of rare EYA4 variants are poorly understood and their prevalence in a large cohort has not been previously reported. We investigated cardio-auditory phenotypes in 11,451 individuals in a large biobank using a rare variant, genome-first approach to EYA4. We filtered 256 EYA4 variants carried by 6737 participants to 26 rare and predicted deleterious variants carried by 42 heterozygotes. We aggregated predicted deleterious EYA4 gene variants into a combined variable (i.e. "gene burden") and performed association studies across phenotypes compared to wildtype controls. We validated findings with replication in three independent cohorts and human tissue expression data. EYA4 gene burden was significantly associated with audiometric-proven HL (p = [Formula: see text], Mobitz Type II AV block (p = [Formula: see text]) and the syndromic presentation of HL and primary cardiomyopathy (p = 0.0194). Analyses on audiogram, echocardiogram, and electrocardiogram data validated these associations. Prior reports have focused on identifying variants in families with severe or syndromic phenotypes. In contrast, we found, using a genotype-first approach, that gene burden in EYA4 is associated with more subtle cardio-auditory phenotypes in an adult medical biobank population, including cardiac conduction disorders which have not been previously reported. We show the value of using a focused approach to uncover human disease related to pleiotropic gene variants and suggest a role for genetic testing in adults presenting with hearing loss.

Enlargement of the aorta is an important risk factor for aortic aneurysm and dissection, a leading cause of morbidity in the developed world. Here we performed automated extraction of ascending aortic diameter from cardiac magnetic resonance images of 36,021 individuals from the UK Biobank, followed by genome-wide association. We identified lead variants across 41 loci, including genes related to cardiovascular development (HAND2, TBX20) and Mendelian forms of thoracic aortic disease (ELN, FBN1). A polygenic score significantly predicted prevalent risk of thoracic aortic aneurysm and the need for surgical intervention for patients with thoracic aneurysm across multiple ancestries within the UK Biobank, FinnGen, the Penn Medicine Biobank and the Million Veterans Program (MVP). Additionally, we highlight the primary causal role of blood pressure in reducing aortic dilation using Mendelian randomization. Overall, our findings provide a roadmap for using genetic determinants of human anatomy to understand cardiovascular development while improving prediction of diseases of the thoracic aorta.

More than 800 million people in the world suffer from chronic kidney disease (CKD). Genome-wide association studies (GWAS) have identified hundreds of loci where genetic variants are associated with kidney function, however, causal genes and pathways for CKD remain unknown. Here we performed integration of kidney function GWAS studies and human kidney-specific expression quantitative trait analysis (eQTL) and identified that the expression of beta mannosidase (MANBA) was lower in kidneys of subjects with CKD risk genotype. We also show an increased incidence of renal failure in subjects with rare heterozygous loss of function coding variants in MANBA using phenome-wide association analysis (PheWAS) of 40,963 subjects with exome sequencing data. MANBA is a lysosomal gene highly expressed in kidney tubule cells. Deep phenotyping revealed structural and functional lysosomal alterations in human kidneys from subjects with CKD risk alleles and mice with genetic deletion of Manba. Manba heterozygous and knock-out mice developed more severe kidney fibrosis when subjected to toxic injury induced by cisplatin or folic acid. Manba loss altered multiple pathways, including endocytosis and autophagy. In the absence of Manba, toxic acute tubule injury induced inflammasome activation and fibrosis. Taken together, these results illustrate the convergence of common non-coding and rare coding variants in MANBA in kidney disease development and demonstrate the role of the endolysosomal system in kidney disease development.

As more research studies incorporate next-generation sequencing (including whole-genome or whole-exome sequencing), investigators and institutional review boards face difficult questions regarding which genomic results to return to research participants and how. An American College of Medical Genetics and Genomics 2013 policy paper suggesting that pathogenic mutations in 56 specified genes should be returned in the clinical setting has raised the question of whether comparable recommendations should be considered in research settings. The Clinical Sequencing Exploratory Research (CSER) Consortium and the Electronic Medical Records and Genomics (eMERGE) Network are multisite research programs that aim to develop practical strategies for addressing questions concerning the return of results in genomic research. CSER and eMERGE committees have identified areas of consensus regarding the return of genomic results to research participants. In most circumstances, if results meet an actionability threshold for return and the research participant has consented to return, genomic results, along with referral for appropriate clinical follow-up, should be offered to participants. However, participants have a right to decline the receipt of genomic results, even when doing so might be viewed as a threat to the participants’ health. Research investigators should be prepared to return research results and incidental findings discovered in the course of their research and meeting an actionability threshold, but they have no ethical obligation to actively search for such results. These positions are consistent with the recognition that clinical research is distinct from medical care in both its aims and its guiding moral principles.

We conducted a genomewide association study in 179 individuals with ACE inhibitor-associated angioedema and 489 ACE inhibitor-exposed controls from Nashville, TN and Marshfield, WI. We performed a replication study in 19 cases and 57 age-, sex-, and ancestry-matched controls from the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET). There were no genomewide significant associations (p-8 ) of any SNP with angioedema in either African or European Americans. Sixteen SNPs in African Americans and 41 SNPs in European Americans that were moderately associated with angioedema (p-4 ) were evaluated for replication in ONTARGET. The T allele of rs500766, a SNP in the gene encoding for protein kinase C θ, was associated with a reduced risk of angioedema in both the Nashville/Marshfield sample (OR 0.42, 95% CI 0.28-0.63, p=2.97x10 -5 in the additive model and OR 0.42, 95% CI 0.26-0.67, p=3.04x10 -4 in the dominant model) and in ONTARGET (OR 0.28, 95% CI 0.09-0.89, p=0.030 in the dominant model). The G allele of rs2724635, a SNP in ETS variant gene 6, was associated with increased risk of ACE inhibitor-associated angioedema in both the Nashville/Marshfield sample (OR 2.78, 95%CI 1.67-4.00, p=2.73x10 -5 in the additive model; OR 3.23, 95%CI 1.75-6.25, p=2.11x10 -4 dominant model; OR 5.56, 95%CI 1.85-16.6, p=2.01x10 -3 recessive mode) and in the ONTARGET sample (OR 3.27, 95%CI 1.03-10.35, p=0.044 in the recessive model). We also conducted a candidate-gene study, using the smaller ONTARGET sample for discovery, and the Nashville/Marshfield study for replication. In the candidate gene study, rs989692 in the gene encoding for neprilysin ( MME ), was significantly associated with angioedema in ONTARGET and in African Americans in the Nashville/Marshfield sample. Variants in genes involved in immune regulation and in neprilysin, an enzyme that degrades bradykinin and substance P, were associated with ACE inhibitor-associated angioedema.