BackgroundEarly‐onset (≤65 years old) Alzheimer Disease (EOAD), which accounts for approximately 10% of all AD cases, is sometimes equated with dominantly inherited forms of AD (i.e., caused by known mutations in APP, PSEN1 or PSEN2). However, 90% of EOAD cases remain unexplained by these variants. This project aims to identify novel EOAD‐associated variants through a large‐scale, multi‐ethnic genome‐wide association (GWA) study.MethodWe have leveraged the Alzheimer Disease Genetics Consortium (ADGC) GWAS dataset that is aligned to GRCh38 and imputed with the TOPMed imputation server. This includes 39 studies from non‐Hispanic Whites (NHW; CA = 3,202; CO = 5,782), 17 from African American (CA = 139; CO = 253), six from Asian (CA = 133; CO = 474), and seven from Hispanic (CA = 199; CO = 59) cohorts. Only the younger (≤65yo) and older participants (>80yo) were included for analysis as cases and controls, respectively. The genetic background was confirmed using PCA. We are performing single‐variant analysis to identify variants that confer a higher risk for EOAD.ResultOur preliminary single‐variant association analysis (using sex, PC1‐PC10 as covariates) emerging from the largest NHW cohort (CA = 3,202; CO = 5,782) have revealed nine different loci that were associated with EOAD at a suggestive P‐value<1×10−6. The strongest signal from our analysis was in the APOE region. Additionally, we identified three novel genome‐wide significant (P‐value <5×10−8) loci of interest at HLA‐DRB9 (rs9268852, P‐value = 2.9×10−9, OR = 1.22); FAM86B3P (rs73199790, P‐value = 3×10−11, OR = 1.32); and MSMB (rs2075895, P‐value = 2.83×10−16, OR = 1.26); while also confirming the previously identified loci at MS4A4A (rs7108663, P‐value = 1.13×10−10, OR = 0.80) and CR1 (rs6656401, P‐value = 2.54×10−12, OR = 1.32). We will perform qualitative associations on the other three ethnicities to confirm the transferability of these signals.ConclusionOur single‐variant analysis has identified three novel loci associated with EOAD. This study is the largest genetic screening for risk and protective variants in EOAD and will be instrumental to identifying novel variants and pathways implicated in unexplained EOAD. Our future analysis includes gene‐based association and pathway analyses per ethnicity to identify variants that confer a higher risk for EOAD, followed by transethnic analysis to validate the comprehensive nature of these risk factors. Additionally, we have also generated GWAS data from the Knight‐ADRC participants, which will be merged with the ADGC datasets for our future analysis.

10029 Background: Type 2 diabetes (T2D) is an established late effect of cancer treatment among long-term survivors of childhood cancer. Genetic factors underpinning T2D in diverse populations of survivors have not been well studied. Methods: We conducted a multi-ancestry genome-wide association study (GWAS) for clinically ascertained T2D among survivors of European (EUR; N = 3,102 with 261 cases) and African (AFR; N = 574 with 43 cases) ancestry from SJLIFE. Replication analyses were performed between ancestries in SJLIFE and in EUR survivors in CCSS (N = 5,965; 270 self-reported cases). Two published T2D polygenic risk scores (PRSs) were assessed in survivors: a 338-variant multi-ancestry PRS (N~1.4 million; 49% non-EUR descent) and a ~6.9 million-variant EUR-only PRS (N~160K; DIAGRAM Consortium and UK Biobank Study). Treatment-related T2D risk effect modification was evaluated for abdominal irradiation and alkylating agents. Results: In SJLIFE AFR survivors, one novel locus with suggestive significance was identified (5p15.2: OR = 10.19, P = 5.1x10-7), replicating in both SJLIFE EUR (P = 0.011) and CCSS EUR survivors (P = 0.021). A EUR-specific genome-wide significant association at 8q11.21 ( SNTG1 intronic variant; OR = 1.99; P = 4.4x10-8) was replicated in CCSS (P = 8.1x10-3). Two other loci with suggestive associations (P < 5x10-6) in SJLIFE EUR survivors replicated in SJLIFE AFR survivors (P < 0.05), achieving genome-wide significance in multi-ancestry meta-analysis (2p25.3: OR = 2.05, P = 4.5x10-8; 19p12: OR = 2.43 P = 5.7x10-9). Each of the three novel trans-ancestral loci overlapped putative Polycomb-repressed regions, i.e., chromatin-based gene regulation elements, in pancreatic cells and displayed treatment-related effect heterogeneity across ancestry groups. Notably, AFR survivors with risk alleles experienced disproportionately greater T2D risk if treated with alkylating agents (2p25.3: OR = 3.95; 19p12: OR = 5.74; 5p15.2: OR = 17.81). Increases in the T2D odds per multi-ancestry PRS standard deviation were consistent in survivors across ancestries (SJLIFE EUR: OR = 1.84, P = 1.1x10-16; SJLIFE AFR: OR = 1.80, P = 2.8x10-3, CCSS EUR: OR = 1.60, P = 8.4x10-13). However, T2D risk association with the EUR-only PRS was absent in AFR survivors (OR = 0.97, P = 0.95). Conclusions: Multi-ancestry genetic analyses revealed three novel T2D risk alleles associated with disproportionately greater alkylating agent-related risk among African-ancestry survivors. Furthermore, an external multi-ancestry T2D PRS was associated with increased risk in diverse ancestry survivors, whereas a EUR-only PRS was not useful for African-ancestry survivors. This study supports precision diabetes surveillance and survivorship care for all childhood cancer survivors, including those in minority ancestry groups.

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