PT - JOURNAL ARTICLE AU - Niladri Banerjee AU - Tatiana Polushina AU - Francesco Bettella AU - Sudheer Giddaluru AU - Vidar M. Steen AU - Ole A. Andreassen AU - Stephanie Le Hellard TI - Recently evolved human-specific methylated regions are enriched in schizophrenia signals AID - 10.1101/113175 DP - 2018 Jan 01 TA - bioRxiv PG - 113175 4099 - http://biorxiv.org/content/early/2018/04/21/113175.short 4100 - http://biorxiv.org/content/early/2018/04/21/113175.full AB - Background One explanation for the persistence of schizophrenia despite the reduced fertility of patients is that it is a by-product of recent human evolution. This hypothesis is supported by evidence suggesting that recently-evolved genomic regions in humans are involved in the genetic risk for schizophrenia. Using summary statistics from genome-wide association studies (GWAS) of schizophrenia and 11 other phenotypes, we tested for enrichment of association with GWAS traits in regions that have undergone methylation changes in the human lineage compared to Neanderthals and Denisovans, i.e. human-specific differentially methylated regions (DMRs). We used analytical tools that evaluate polygenic enrichment of a subset of genomic variants against all variants.Results Schizophrenia was the only trait in which DMR SNPs showed clear enrichment of association that passed the genome-wide significance threshold. The enrichment was not observed for Neanderthal or Denisovan DMRs. The enrichment seen in human DMRs is comparable to that for genomic regions tagged by Neanderthal Selective Sweep markers, and stronger than that for Human Accelerated Regions. The enrichment survives multiple testing performed through permutation (n=10,000) and bootstrapping (n=5,000) in INRICH (p<0.01). Some enrichment of association with height was observed at the gene level.Conclusions Regions where DNA methylation modifications have changed during recent human evolution show enrichment of association with schizophrenia and possibly with height. Our study further supports the hypothesis that genetic variants conferring risk of schizophrenia co-occur in genomic regions that have changed as the human species evolved. Since methylation is an epigenetic mark, potentially mediated by environmental changes, our results also suggest that interaction with the environment might have contributed to that association.(3’UTR)3’ untranslated region,(5’UTR)5’ untranslated region,(ADHD)attention deficit hyperactivity disorder,(BMI)body mass index,(BPD)bipolar disorder,(CpG)5’ Cytosine-phosphate-Guanine 3’,(CREB)cyclic adenosine monophosphate responsive element binding protein,(DBP)diastolic blood pressure,(DMR)differentially methylated region,(DNA)deoxyribonucleic acid,(GWAS)genome-wide association studies,(HARs)Human Accelerated Regions,(HDL)high density lipoprotein,(HWE)Hardy-Weinberg equilibrium,(INRICH)Interval enRICHment analysis tool,(IPA)Ingenuity Pathway Analysis,(LD)linkage disequilibrium,(LDL)low density lipoprotein,(MAF)minor allele frequency,(MHC)Major histocompatibility complex,(NSS)Neanderthal Selective Sweep,(QQ)quantile-quantile,(RA)rheumatoid arthritis,(SBP)systolic blood pressure,(SCZ)schizophrenia,(SNP)single nucleotide polymorphism,(TC)total cholesterol,(TG)triglycerides.