Chen, ZhongboZhang, DavidReynolds, Regina HGustavsson, Emil KGarcía-Ruiz, SoniaD'Sa, KarishmaFairbrother-Browne, AineVandrovcova, JanaInternational Parkinson’s Disease Genomics Consortium (IPDGC)Hardy, JohnHoulden, HenryGagliano Taliun, Sarah ABotía, JuanRyten, Mina2025-01-072025-01-072021-04-06https://hdl.handle.net/10668/26219Knowledge of genomic features specific to the human lineage may provide insights into brain-related diseases. We leverage high-depth whole genome sequencing data to generate a combined annotation identifying regions simultaneously depleted for genetic variation (constrained regions) and poorly conserved across primates. We propose that these constrained, non-conserved regions (CNCRs) have been subject to human-specific purifying selection and are enriched for brain-specific elements. We find that CNCRs are depleted from protein-coding genes but enriched within lncRNAs. We demonstrate that per-SNP heritability of a range of brain-relevant phenotypes are enriched within CNCRs. We find that genes implicated in neurological diseases have high CNCR density, including APOE, highlighting an unannotated intron-3 retention event. Using human brain RNA-sequencing data, we show the intron-3-retaining transcript to be more abundant in Alzheimer's disease with more severe tau and amyloid pathological burden. Thus, we demonstrate potential association of human-lineage-specific sequences in brain development and neurological disease.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/Alzheimer DiseaseApolipoproteins EBrainChromosomes, Human, Pair 19Conserved SequenceDNA, IntergenicGene OntologyGenome, HumanHumansIntronsLinkage DisequilibriumMolecular Sequence AnnotationNeurodegenerative DiseasesPhenotypePhylogenyPolymorphism, Single NucleotideRNA, Long NoncodingRNA, MessengerRegression Analysisresearch article33824317open access10.1038/s41467-021-22262-52041-1723PMC8024253https://www.nature.com/articles/s41467-021-22262-5.pdfhttps://pmc.ncbi.nlm.nih.gov/articles/PMC8024253/pdf