• Neanderthal
• pancreatic cancer
• genetic polymorphism
• introgression

Present-day non-sub-Saharans inherited 1-6% of their genomes from extinct forms as a consequence of multiple interbreeding events occurred during the spread of anatomically modern humans (AMH) out of Africa, about 100,000 yBP. Previous studies identified Neanderthal legacy in adaptive variants involved in immune response, chronotypes, and skin/hair pigmentation. Neanderthal alleles have been found to also affect disease-related traits such as mood disorders, tobacco use, obesity and, recently, the risk factor for severe COVID-19. Beyond Neanderthal alleles, the role of other archaic variants emerged out of Africa, after Neanderthal introgression, is poorly explored. We examined whole-genome databanks of modern (1000 Genomes Project) and archaic (David Reich’s Laboratory dataset (https://reich.hms.harvard.edu/datasets, Max Planck Institute for Evolutionary Anthropology http://cdna.eva.mpg.de/neandertal/altai/AltaiNeandertal/VCF/) genomes to assess the role of Neanderthal introgressed variants in modern human disease. We examined archaic variants' contribution to pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, which develops in the exocrine portion of pancreas. We chose to focus on PDAC since several of its risk factors coincide with traits in which Neanderthal variants are suggested to be involved in. To detect Neanderthal introgressed variants we selected biallelic loci in Central European (CEU), and used as reference Yoruba (YRI) genomes, assumed to not bear Neanderthal ancestry. Comparing CEU, YRI, Altai Neanderthal, and ancient European AMH genomes (8,000-2,000 yBP), we selected variants candidate to have been acquired by our species during its spread out of Africa. We detected 264,172 Neanderthal-introgressed variants and 14,173 not Neanderthal-introgressed variants. To assess if the selected variants were genetic risk factors for PDAC, we used as discovery set 8,738 cases and 7,034 controls in the context of Pancreatic Cancer Cohort Consortium (PanScan) I, II and III and Pancreatic Cancer Case-Control Consortium (PanC4). Through a logistic regression, we observed seven Neanderthal SNPs and two ancient AMH SNPs, which showed a strong association (P-value lower than 5×10-4). Six candidate Neanderthal SNPs were replicated in the PANcreatic Disease ReseArch (PANDoRA) consortium, through de novo genotyping of 8,019 samples from 10 countries. Genotyped samples that showed a call rate less than 75% were excluded from the analysis and Hardy Weinberg equilibrium was tested for each SNP. After a logistic regression, we observed the C allele of rs72637203 associated to PDAC in allelic (OR 1.26, 95%C.I. 1.09-1.46, P-value= 0,002), codominant (OR=1.27, 95%C.I. 1.09-1.46, P-value=0,003), and dominant genetic model (OR=1.28, 95%C.I. 1.09-1.49, P-value=0,002). The Neanderthal variants were investigated through a gene-set analysis on PanScan and PanC4 data to assess the association between genes with at least a Neanderthal variant and PDAC, using MAGMA software. Neanderthal genes with a P-value lower than 1×10-4 underwent an enrichment analysis. Interestingly, Neanderthal genes resulted to be significantly involved in maturity on-set diabetes of the young (MODY).