Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage

International Parkinson's Disease Genomics Consortium (IPDGC)

doi:10.1038/s41467-021-22262-5

Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage

International Parkinson's Disease Genomics Consortium (IPDGC)

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Knowledge 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.

Original language	English (US)
Article number	2076
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-22262-5
State	Published - Dec 1 2021

Funding

The authors are grateful to the participants in the Religious Order Study, the Memory and Aging Project. Z.C. and R.H.R. were supported by grants from the Leonard Wolfson Foundation. M.R. was supported by the United Kingdom Medical Research Council (MRC) through the award of a Tenure Track Clinician Scientist Fellowship (MR/ N008324/1). J.H. was supported by the UK Dementia Research Institute which receives its funding from DRI Limited, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. J.H. has also been funded by the Medical Research Council (award MR/N026004/1), Wellcome Trust (award 202903/Z/16/Z), Dolby Family Fund and National Institute for Health Research University College London Hospitals Biomedical Research Centre. J.B. is supported through the Science and Technology Agency, Séneca Foundation, CARM, Spain (research project 00007/COVI/20). The authors are grateful to Dr Julia di Iulio for providing genomic territory annotation files used to generate Fig. 2a.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-021-22262-5

Cite this

@article{6de65c5971a44a77a2160bfcb0c4c42d,

title = "Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage",

abstract = "Knowledge 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{\textquoteright}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.",

author = "{International Parkinson's Disease Genomics Consortium (IPDGC)} and Zhongbo Chen and David Zhang and Reynolds, {Regina H.} and Gustavsson, {Emil K.} and Sonia Garc{\'i}a-Ruiz and Karishma D{\textquoteright}Sa and Aine Fairbrother-Browne and Jana Vandrovcova and Noyce, {Alastair J.} and Rauan Kaiyrzhanov and Ben Middlehurst and Kia, {Demis A.} and Manuela Tan and Morris, {Huw R.} and Helene Plun-Favreau and Peter Holmans and Daniah Trabzuni and Jose Bras and John Quinn and Mok, {Kin Y.} and Kinghorn, {Kerri J.} and Kimberley Billingsley and Wood, {Nicholas W.} and Patrick Lewis and Sebastian Schreglmann and Rita Guerreiro and Ruth Lovering and Lea R{\textquoteright}Bibo and Claudia Manzoni and Mie Rizig and Sebastian Guelfi and Valentina Escott-Price and Viorica Chelban and Thomas Foltynie and Nigel Williams and Alexis Brice and Fabrice Danjou and Suzanne Lesage and Corvol, {Jean Christophe} and Maria Martinez and Claudia Schulte and Kathrin Brockmann and Javier Sim{\'o}n-S{\'a}nchez and Peter Heutink and Patrizia Rizzu and Manu Sharma and Thomas Gasser and Aude Nicolas and Steven Lubbe and Mencacci, {Niccolo E.}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

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doi = "10.1038/s41467-021-22262-5",

language = "English (US)",

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journal = "Nature communications",

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AU - International Parkinson's Disease Genomics Consortium (IPDGC)

AU - Chen, Zhongbo

AU - Zhang, David

AU - Reynolds, Regina H.

AU - Gustavsson, Emil K.

AU - García-Ruiz, Sonia

AU - D’Sa, Karishma

AU - Fairbrother-Browne, Aine

AU - Vandrovcova, Jana

AU - Noyce, Alastair J.

AU - Kaiyrzhanov, Rauan

AU - Middlehurst, Ben

AU - Kia, Demis A.

AU - Tan, Manuela

AU - Morris, Huw R.

AU - Plun-Favreau, Helene

AU - Holmans, Peter

AU - Trabzuni, Daniah

AU - Bras, Jose

AU - Quinn, John

AU - Mok, Kin Y.

AU - Kinghorn, Kerri J.

AU - Billingsley, Kimberley

AU - Wood, Nicholas W.

AU - Lewis, Patrick

AU - Schreglmann, Sebastian

AU - Guerreiro, Rita

AU - Lovering, Ruth

AU - R’Bibo, Lea

AU - Manzoni, Claudia

AU - Rizig, Mie

AU - Guelfi, Sebastian

AU - Escott-Price, Valentina

AU - Chelban, Viorica

AU - Foltynie, Thomas

AU - Williams, Nigel

AU - Brice, Alexis

AU - Danjou, Fabrice

AU - Lesage, Suzanne

AU - Corvol, Jean Christophe

AU - Martinez, Maria

AU - Schulte, Claudia

AU - Brockmann, Kathrin

AU - Simón-Sánchez, Javier

AU - Heutink, Peter

AU - Rizzu, Patrizia

AU - Sharma, Manu

AU - Gasser, Thomas

AU - Nicolas, Aude

AU - Lubbe, Steven

AU - Mencacci, Niccolo E.

PY - 2021/12/1

Y1 - 2021/12/1

N2 - Knowledge 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.

AB - Knowledge 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.

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JF - Nature communications

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Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage

Abstract

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UN SDGs

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