EGAGenomicsElena Bosch Fustéhttps://ega-archive.org/dacs/EGAC00001000244EGAEGA DAC EGAC00001000244EGAelena.bosch@upf.eduParkinson's disease (PD) can be divided into familial (Mendelian) and sporadic forms. A number of causal genes have been discovered for the Mendelian form, which constitutes 10-20% of the total cases. Genome-wide association studies have successfully uncovered a number of susceptibility loci for sporadic cases but those only explain a small fraction (6-7%) of PD heritability. It has been observed that some genes that confer susceptibility to PD through common risk variants also contain rare causing mutations for the Mendelian forms of the disease. These results suggest a possible functional link between Mendelian and sporadic PD and led us to investigate the role that rare and low-frequency variants could have on the sporadic form. Through a targeting approach, we have resequenced at 49× coverage the exons and regulatory regions of 38 genes (including Mendelian and susceptibility PD genes) in 249 sporadic PD patients and 145 unrelated controls of European origin. Unlike susceptibility genes, Mendelian genes show a clear general enrichment of rare functional variants in PD cases, observed directly as well as with Tajima's D statistic and several collapsing methods. Our findings suggest that rare variation on PD Mendelian genes may have a role in the sporadic forms of the disease.Essential trace elements possess vital functions at molecular, cellular, and physiological levels in health and disease, and they are tightly regulated in the human body. In order to assess variability and potential adaptive evolution of trace element homeostasis, we quantified 18 trace elements in 150 liver samples, together with the expression levels of 90 genes and abundances of 40 proteins involved in their homeostasis. Additionally, we genotyped 169 single nucleotide polymorphism (SNPs) in the same sample set. We detected significant associations for 8 protein quantitative trait loci (pQTL), 10 expression quantitative trait loci (eQTLs), and 15 micronutrient quantitative trait loci (nutriQTL). Six of these exceeded the false discovery rate cutoff and were related to essential trace elements: 1) one pQTL for GPX2 (rs10133290); 2) two previously described eQTLs for HFE (rs12346) and SELO (rs4838862) expression; and 3) three nutriQTLs: The pathogenic C282Y mutation at HFE affecting iron (rs1800562), and two SNPs within several clustered metallothionein genes determining selenium concentration (rs1811322 and rs904773). Within the complete set of significant QTLs (which involved 30 SNPs and 20 gene regions), we identified 12 SNPs with extreme patterns of population differentiation (FST values in the top 5% percentile in at least one HapMap population pair) and significant evidence for selective sweeps involving QTLs at GPX1, SELENBP1, GPX3, SLC30A9, and SLC39A8. Overall, this detailed study of various molecular phenotypes illustrates the role of regulatory variants in explaining differences in trace element homeostasis among populations and in the human adaptive response to environmental pressures related to micronutrients.Signatures of Evolutionary Adaptation in Quantitative Trait Loci Influencing Trace Element Homeostasis in Liver.Mendelian genes for Parkinson's disease contribute to the sporadic forms of the disease.Spataro Nino N, Calafell Francesc F, Cervera-Carles Laura L, Casals Ferran F, Pagonabarraga Javier J, Pascual-Sedano Berta B, Campolongo Antònia A, Kulisevsky Jaime J, Lleó Alberto A, Navarro Arcadi A, Clarimón Jordi J, Bosch Elena EEngelken Johannes J, Espadas Guadalupe G, Mancuso Francesco M FM, Bonet Nuria N, Scherr Anna-Lena AL, Jímenez-Álvarez Victoria V, Codina-Solà Marta M, Medina-Stacey Daniel D, Spataro Nino N, Stoneking Mark M, Calafell Francesc F, Sabidó Eduard E, Bosch Elena EfalseUPF - Evolutionary Population Genetics lab Data Access CommitteeData Access Committee EGAC00001000244EGAC0000100024496062658256225504046EGAS00001001292EGAS00001000973EGAD00010000853EGAD00001001029