OBJECTIVES/GOALS: We aimed to conduct an updated genome-wide meta-analysis of keloids in expanded populations, including those most afflicted by keloids. Our overall objective was to improve understanding of keloid development though the identification and further characterization of keloid-associated genes with genetically predicted gene expression (GPGE). METHODS/STUDY POPULATION: We used publicly available summary statistics from several large-scale DNA biobanks, including the UK Biobank, FinnGen, and Biobank Japan. We also leveraged data from the Million Veterans Program and performed genome-wide association studies of keloids in BioVU and eMERGE. For each of these datasets, cases were determined from ICD-9/ICD-10 codes and phecodes. With these data we conducted fixed effects meta-analysis, both across ancestries and stratified by broad ancestry groups. This approach allowed us to consider cumulative evidence for genetic risk factors for keloids and explore potential ancestry-specific components of risk. We used FUMA for functional annotation of results and LDSC to estimate ancestry-specific heritability. We performed GPGE analysis using S-PrediXcan with GTEx v8 tissues. RESULTS/ANTICIPATED RESULTS: We detected 30 (23 novel) genomic risk loci in the cross-ancestry analysis. Major risk loci were broadly consistent between ancestries, with variable effects. Keloid heritability estimates from LDSC were 6%, 21%, and 34% for European, East Asian, and African ancestry, respectively. The top hit (P = 1.7e-77) in the cross-ancestry analysis was at a replicated variant (rs10863683) located downstream of LINC01705. GPGE analysis identified an association between decreased risk of keloids and increased expression of LINC01705 in fibroblasts (P = 3.6e10-20), which are important in wound healing. The top hit in the African-ancestry analysis (P = 5.5e-31) was a novel variant (rs34647667) in a conserved region downstream of ITGA11. ITGA11 encodes a collagen receptor and was previously associated with uterine fibroids. DISCUSSION/SIGNIFICANCE: This work significantly increases the yield of discoveries from keloid genetic association studies, describing both common and ancestry-specific effects. Stark differences in heritability support a potential adaptive origin for keloid disparities. Further work will continue to examine keloids in the broader context of other fibrotic diseases.

Post-traumatic stress disorder (PTSD) after traumatic birth can have a debilitating effect on parents already adapting to significant life changes during the post-partum period. Cognitive therapy for PTSD (CT-PTSD) is a highly effective psychological therapy for PTSD which is recommended in the NICE guidelines (National Institute for Health and Care Excellence, 2018) as a first-line intervention for PTSD. In this paper, we provide guidance on how to deliver CT-PTSD for birth-related trauma and baby loss and how to address common cognitive themes.

OBJECTIVES/GOALS: Preeclampsia (PE) is a hypertensive disorder of pregnancy, affecting 5 - 7% of pregnancies worldwide. A major cause of morbidity and mortality, PE is also associated with subsequent adverse health outcomes, including long-term increased risk of cardiovascular disease. The genetics conferring increased risk for PE are incompletely understood. METHODS/STUDY POPULATION: We performed a cross-ancestry, fixed-effects meta-analysis, incorporating both published and unpublished genome-wide association study (GWAS) summary statistics. In addition to publicly available summary statistics from two prior studies, we generated GWAS data from three electronic health record biobanks (BioVU, eMERGE, and PMBB). In total, we utilized data from 359,378 individuals (4,411 cases and 354,967 controls). Leveraging this large-scale biobank data importantly allows for detection of complex factors contributing to the diverse etiology of PE. Cases across cohorts were defined using PE-specific ICD-9/ICD-10 codes and phecodes. Cohorts included pregnant individuals of self-identified non-Hispanic Black, non-Hispanic White, and East Asian ancestry. RESULTS/ANTICIPATED RESULTS: 2 of 20,204,625 loci achieved genome-wide significance (p < 5 × 10–8) when minor allele frequency was limited to common variants (>0.01). The most significant locus was rs138180605 (p = 1.77 × 10–8), located in an intergenic region between FGFR2 and ATE1, both previously associated with breast cancer. The other significant locus was rs137895377 (p = 2.33 × 10–8), located in an intronic region of PLEKHO1. Another 225 loci achieved suggestive significance (p < 1 × 10–5). 203 loci could be mapped to 109 unique genes, some previously associated with related phenotypes such as hypertension. Next steps will focus on functional analyses, including genetically predicted gene expression incorporating placental tissue, followed by construction of a PE polygenic risk score to demonstrate predictive utility of results. DISCUSSION/SIGNIFICANCE: This work has contributed to the limited body of knowledge surrounding maternal genetic susceptibility to PE by identifying several loci warranting further investigation. Further work will expand on these results to improve understanding of genetic factors and clarify clinical risk of disease.