A multi-cohort genome-wide association study in African ancestry individuals reveals risk loci for primary open-angle glaucoma

Cell · 2024 · 62 citations

• Biology
• Genetics
• Evolutionary biology

Polygenic prediction of preeclampsia and gestational hypertension

Nature Medicine · 2023 · 115 citations

• Medicine
• Obstetrics
• Bioinformatics

Mapping the human genetic architecture of COVID-19

Nature · 2021 · 1108 citations

• Biology
• Virology
• Evolutionary biology

. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

Polygenic Risk of Psychiatric Disorders Exhibits Cross-trait Associations in Electronic Health Record Data From European Ancestry Individuals

Biological Psychiatry · 2020 · 54 citations

• Medicine
• Psychiatry
• Clinical psychology

BACKGROUND: Prediction of disease risk is a key component of precision medicine. Common traits such as psychiatric disorders have a complex polygenic architecture, making the identification of a single risk predictor difficult. Polygenic risk scores (PRSs) denoting the sum of an individual's genetic liability for a disorder are a promising biomarker for psychiatric disorders, but they require evaluation in a clinical setting. METHODS: We developed PRSs for 6 psychiatric disorders (schizophrenia, bipolar disorder, major depressive disorder, cross disorder, attention-deficit/hyperactivity disorder, and anorexia nervosa) and 17 nonpsychiatric traits in more than 10,000 individuals from the Penn Medicine Biobank with accompanying electronic health records. We performed phenome-wide association analyses to test their association across disease categories. RESULTS: Four of the 6 psychiatric PRSs were associated with their primary phenotypes (odds ratios from 1.2 to 1.6). Cross-trait associations were identified both within the psychiatric domain and across trait domains. PRSs for coronary artery disease and years of education were significantly associated with psychiatric disorders, largely driven by an association with tobacco use disorder. CONCLUSIONS: We demonstrated that the genetic architecture of electronic health record-derived psychiatric diagnoses is similar to ascertained research cohorts from large consortia. Psychiatric PRSs are moderately associated with psychiatric diagnoses but are not yet clinically predictive in naïve patients. Cross-trait associations for these PRSs suggest a broader effect of genetic liability beyond traditional diagnostic boundaries. As identification of genetic markers increases, including PRSs alongside other clinical risk factors may enhance prediction of psychiatric disorders and associated conditions in clinical registries.

Genetic Architecture of Abdominal Aortic Aneurysm in the Million Veteran Program

Circulation · 2020 · 142 citations

• Medicine
• Internal medicine
• Cardiology

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: ). 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.