Leveraging polygenic enrichments of gene features to predict genes underlying complex traits and diseases

Weeks, Elle M.; Ulirsch, Jacob C.; Cheng, Nathan; Trippe, Brian L.; Fine, Rebecca S.; Miao, Jenkai; Patwardhan, Tejal A.; Kanai, Masahiro; Nasser, Joseph; Fulco, Charles P.; Tashman, Katherine; Aguet, François; Li, Taibo; Ordovás-Montañés, José; Smillie, Christopher S.; Biton, Moshe; Shalek, Alex K.; Ananthakrishnan, Ashwin N.; Xavier, Ramnik J.; Regev, Aviv; Gupta, Rajat M.; Lage, Kasper; Ardlie, Kristin; Hirschhorn, Joel N.; Lander, Eric S.; Engreitz, Jesse M.; Finucane, Hilary

doi:10.1038/s41588-023-01443-6

Cited by 76 publications

(69 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4C. When searching these variants across the phenoscanner portal (www.phenoscanner.medschl.cam.ac.uk), rs62075723-G (allele frequency 36%), an intron variant in TSPAN10 linked to the ACTG1 gene by the Polygenic Priority Score (PoPS), a method for prioritizing putative causal genes ( 24 ) (see Supplementary Materials and Methods), associated with a thicker GCL (beta = 0.13 SD per A allele, P = 3.93 × 10 −63 ) and thinner PS layer (beta = −0.07 per A allele, P = 9.53 × 10 −20 ), was also associated with increased risk of AMD [odds ratio (OR), 1.12; 95% CI, 1.09 to 1.16; P = 2.5 × 10 −11 ]. Furthermore, rs17421627-G, a LINC00461 intron variant linked to MEF2C by PoPS, associated with increased thickness of the INL (beta = 0.41SD, P = 7.5 × 10 −193 ), was also associated with a 3-μm increase in retinal vascular caliber ( P = 7.0 × 10 −16 ) ( 25 ).…”

Section: Resultsmentioning

confidence: 99%

“…Analyses were restricted to genetic variants with minor allele frequency > 0.001 and consenting unrelated individuals after randomly removing one of each pair of first- or second-degree relatives. Further details on secondary in silico analyses including heritability analysis ( 77 ), prioritization of putative causal genes using PoPS ( 24 ), enrichment analysis, genetic correlation analysis, PRS phenome-wide association study (PRS-PheWAS), and rare variant association study ( 78 – 80 ), are provided in Supplementary Materials and Methods. Replication of UK Biobank GWAS associations was performed in the LIFE-Adult-Study ( 28 ).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Phenome- and genome-wide analyses of retinal optical coherence tomography images identify links between ocular and systemic health

Zekavat,

Jorshery,

Rauscher

et al. 2024

Sci. Transl. Med.

View full text Add to dashboard Cite

The human retina is a multilayered tissue that offers a unique window into systemic health. Optical coherence tomography (OCT) is widely used in eye care and allows the noninvasive, rapid capture of retinal anatomy in exquisite detail. We conducted genotypic and phenotypic analyses of retinal layer thicknesses using macular OCT images from 44,823 UK Biobank participants. We performed OCT layer cross-phenotype association analyses (OCT-XWAS), associating retinal thicknesses with 1866 incident conditions (median 10-year follow-up) and 88 quantitative traits and blood biomarkers. We performed genome-wide association studies (GWASs), identifying inherited genetic markers that influence retinal layer thicknesses and replicated our associations among the LIFE-Adult Study ( N = 6313). Last, we performed a comparative analysis of phenome- and genome-wide associations to identify putative causal links between retinal layer thicknesses and both ocular and systemic conditions. Independent associations with incident mortality were detected for thinner photoreceptor segments (PSs) and, separately, ganglion cell complex layers. Phenotypic associations were detected between thinner retinal layers and ocular, neuropsychiatric, cardiometabolic, and pulmonary conditions. A GWAS of retinal layer thicknesses yielded 259 unique loci. Consistency between epidemiologic and genetic associations suggested links between a thinner retinal nerve fiber layer with glaucoma, thinner PS with age-related macular degeneration, and poor cardiometabolic and pulmonary function with a thinner PS. In conclusion, we identified multiple inherited genetic loci and acquired systemic cardio-metabolic-pulmonary conditions associated with thinner retinal layers and identify retinal layers wherein thinning is predictive of future ocular and systemic conditions.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Phenome- and genome-wide analyses of retinal optical coherence tomography images identify links between ocular and systemic health

Zekavat,

Jorshery,

Rauscher

et al. 2024

Sci. Transl. Med.

View full text Add to dashboard Cite

show abstract

“…We used the nearest protein-coding gene and Polygenic Priority Score (PoPS) approaches to prioritize likely causal genes in the 7 association loci . The genes WARS2 , TRIB2 , RBM6 , MIER3 , EBF1 , EBF2 , and CEBPA were most strongly prioritized by PoPS in their respective loci (eTable 10 in Supplement 2).…”

Section: Resultsmentioning

confidence: 99%

Cardiovascular Significance and Genetics of Epicardial and Pericardial Adiposity

Rämö,

Kany,

Hou

et al. 2024

JAMA Cardiol

View full text Add to dashboard Cite

ImportanceEpicardial and pericardial adipose tissue (EPAT) has been associated with cardiovascular diseases such as atrial fibrillation or flutter (AF) and coronary artery disease (CAD), but studies have been limited in sample size or drawn from selected populations. It has been suggested that the association between EPAT and cardiovascular disease could be mediated by local or paracrine effects.ObjectiveTo evaluate the association of EPAT with prevalent and incident cardiovascular disease and to elucidate the genetic basis of EPAT in a large population cohort.Design, Setting, and ParticipantsA deep learning model was trained to quantify EPAT area from 4-chamber magnetic resonance images using semantic segmentation. Cross-sectional and prospective cardiovascular disease associations were evaluated, controlling for sex and age. Prospective associations were additionally controlled for abdominal visceral adipose tissue (VAT) volumes. A genome-wide association study was performed, and a polygenic score (PGS) for EPAT was examined in independent FinnGen cohort study participants. Data analyses were conducted from March 2022 to December 2023.ExposuresThe primary exposures were magnetic resonance imaging–derived continuous measurements of epicardial and pericardial adipose tissue area and visceral adipose tissue volume.Main Outcomes and MeasuresPrevalent and incident CAD, AF, heart failure (HF), stroke, and type 2 diabetes (T2D).ResultsAfter exclusions, this study included 44 475 participants (mean [SD] age, 64.1 [7.7] years; 22 972 female [51.7%]) from the UK Biobank. Cross-sectional and prospective cardiovascular disease associations were evaluated for a mean (SD) of 3.2 (1.5) years of follow-up. Prospective associations were additionally controlled for abdominal VAT volumes for 38 527 participants. A PGS for EPAT was examined in 453 733 independent FinnGen cohort study participants. EPAT was positively associated with male sex (β = +0.78 SD in EPAT; P &lt; 3 × 10−324), age (Pearson r = 0.15; P = 9.3 × 10−229), body mass index (Pearson r = 0.47; P &lt; 3 × 10−324), and VAT (Pearson r = 0.72; P &lt; 3 × 10−324). EPAT was more elevated in prevalent HF (β = +0.46 SD units) and T2D (β = +0.56) than in CAD (β = +0.23) or AF (β = +0.18). EPAT was associated with incident HF (hazard ratio [HR], 1.29 per +1 SD in EPAT; 95% CI, 1.17-1.43), T2D (HR, 1.63; 95% CI, 1.51-1.76), and CAD (HR, 1.19; 95% CI, 1.11-1.28). However, the associations were no longer significant when controlling for VAT. Seven genetic loci were identified for EPAT, implicating transcriptional regulators of adipocyte morphology and brown adipogenesis (EBF1, EBF2, and CEBPA) and regulators of visceral adiposity (WARS2 and TRIB2). The EPAT PGS was associated with T2D (odds ratio [OR], 1.06; 95% CI, 1.05-1.07; P =3.6 × 10−44), HF (OR, 1.05; 95% CI, 1.04-1.06; P =4.8 × 10−15), CAD (OR, 1.04; 95% CI, 1.03-1.05; P =1.4 × 10−17), AF (OR, 1.04; 95% CI, 1.03-1.06; P =7.6 × 10−12), and stroke in FinnGen (OR, 1.02; 95% CI, 1.01-1.03; P =3.5 × 10−3) per 1 SD in PGS.Conclusions and RelevanceResults of this cohort study suggest that epicardial and pericardial adiposity was associated with incident cardiovascular diseases, but this may largely reflect a metabolically unhealthy adiposity phenotype similar to abdominal visceral adiposity.

show abstract

“…We asked whether cell type-specific DE genes overlapped with risk genes identified by genome-wide association studies (GWAS) of psychiatric disorders. To determine candidate causal genes that mediate the effects of disease-associated genetic variants from recent large-scale GWAS of MDD, BD, and SCZ (51,52,61) we utilized PsyOPS and PoPS, two methods that prioritize casual genes at GWAS lo ci (62,63) (see Methods). Our analysis revealed 22 candidate causal genes exhibiting DE within one or more neuronal subtypes – almost all of which were expressed in interneurons rather than in PYR cells (Figure 3B).…”

Section: Resultsmentioning

confidence: 99%

“… A) Overview of approach. Two recent methods, PsyOPS and PoPS (62,63), are used to predict genes that are causally associated with psychiatric GWAS loci, which are then assessed for overlap with LCM-seq differential expression (DE). B) 29 unique single-nucleotide polymorphisms (SNPs) associated with MDD, BD or SCZ (diagnosis; Dx) were within 500 kb of a cell type-specific DE gene (FDR < 0.20) from that respective disorder and prioritized as causal by either PsyOPS and/or PoPS.…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic pathology of neocortical microcircuit cell types across psychiatric disorders

Arbabi,

Newton,

et al. 2023

Preprint

View full text Add to dashboard Cite

Background: Psychiatric disorders like major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are characterized by altered cognition and mood, brain functions that depend on information processing by cortical microcircuits. We hypothesized that psychiatric disorders would display cell type-specific transcriptional alterations in neuronal subpopulations that make up cortical microcircuits: excitatory pyramidal (PYR) neurons and vasoactive intestinal peptide- (VIP), somatostatin- (SST), and parvalbumin- (PVALB) expressing inhibitory interneurons. Methods: We performed cell type-specific molecular profiling of subgenual anterior cingulate cortex, a region implicated in mood and cognitive control, using laser capture microdissection followed by RNA sequencing (LCM-seq). We sequenced libraries from 130 whole cells pooled per neuronal subtype (VIP, SST, PVALB, superficial and deep PYR) in 76 subjects from the University of Pittsburgh Brain Tissue Donation Program, evenly split between MDD, BD and SCZ subjects and healthy controls. Results: We identified hundreds of differentially expressed (DE) genes and biological pathways across disorders and neuronal subtypes, with the vast majority in inhibitory neuron types, particularly PVALB. DE genes were distinct across cell types, but partially shared across disorders, with nearly all shared genes involved in the formation and maintenance of neuronal circuits. Coordinated alterations in biological pathways were observed between select pairs of microcircuit cell types and partially shared across disorders. Finally, DE genes coincided with known risk variants from psychiatric genome-wide association studies, indicating cell type-specific convergence between genetic and transcriptomic risk for psychiatric disorders. Conclusions: We present the first cell type-specific dataset of cortical microcircuit gene expression across multiple psychiatric disorders. Each neuronal subtype displayed unique dysregulation signatures, some shared across cell types and disorders. Inhibitory interneurons showed more dysregulation than excitatory pyramidal neurons. Our study suggests transdiagnostic cortical microcircuit pathology in SCZ, BD, and MDD and sets the stage for larger-scale studies investigating how cell circuit-based changes contribute to shared psychiatric risk.

show abstract

Leveraging polygenic enrichments of gene features to predict genes underlying complex traits and diseases

Cited by 76 publications

References 64 publications

Phenome- and genome-wide analyses of retinal optical coherence tomography images identify links between ocular and systemic health

Phenome- and genome-wide analyses of retinal optical coherence tomography images identify links between ocular and systemic health

Cardiovascular Significance and Genetics of Epicardial and Pericardial Adiposity

Transcriptomic pathology of neocortical microcircuit cell types across psychiatric disorders

Contact Info

Product

Resources

About