Broad transcriptomic dysregulation occurs across the cerebral cortex in ASD
© 2022. The Author(s)..
Neuropsychiatric disorders classically lack defining brain pathologies, but recent work has demonstrated dysregulation at the molecular level, characterized by transcriptomic and epigenetic alterations1-3. In autism spectrum disorder (ASD), this molecular pathology involves the upregulation of microglial, astrocyte and neural-immune genes, the downregulation of synaptic genes, and attenuation of gene-expression gradients in cortex1,2,4-6. However, whether these changes are limited to cortical association regions or are more widespread remains unknown. To address this issue, we performed RNA-sequencing analysis of 725 brain samples spanning 11 cortical areas from 112 post-mortem samples from individuals with ASD and neurotypical controls. We find widespread transcriptomic changes across the cortex in ASD, exhibiting an anterior-to-posterior gradient, with the greatest differences in primary visual cortex, coincident with an attenuation of the typical transcriptomic differences between cortical regions. Single-nucleus RNA-sequencing and methylation profiling demonstrate that this robust molecular signature reflects changes in cell-type-specific gene expression, particularly affecting excitatory neurons and glia. Both rare and common ASD-associated genetic variation converge within a downregulated co-expression module involving synaptic signalling, and common variation alone is enriched within a module of upregulated protein chaperone genes. These results highlight widespread molecular changes across the cerebral cortex in ASD, extending beyond association cortex to broadly involve primary sensory regions.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2022 |
---|---|
Erschienen: |
2022 |
Enthalten in: |
Zur Gesamtaufnahme - volume:611 |
---|---|
Enthalten in: |
Nature - 611(2022), 7936 vom: 01. Nov., Seite 532-539 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Gandal, Michael J [VerfasserIn] |
---|
Links: |
---|
Themen: |
63231-63-0 |
---|
Anmerkungen: |
Date Completed 29.11.2022 Date Revised 21.03.2024 published: Print-Electronic Citation Status MEDLINE |
---|
doi: |
10.1038/s41586-022-05377-7 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM348377592 |
---|
LEADER | 01000caa a22002652 4500 | ||
---|---|---|---|
001 | NLM348377592 | ||
003 | DE-627 | ||
005 | 20240321235055.0 | ||
007 | cr uuu---uuuuu | ||
008 | 231226s2022 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1038/s41586-022-05377-7 |2 doi | |
028 | 5 | 2 | |a pubmed24n1338.xml |
035 | |a (DE-627)NLM348377592 | ||
035 | |a (NLM)36323788 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Gandal, Michael J |e verfasserin |4 aut | |
245 | 1 | 0 | |a Broad transcriptomic dysregulation occurs across the cerebral cortex in ASD |
264 | 1 | |c 2022 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 29.11.2022 | ||
500 | |a Date Revised 21.03.2024 | ||
500 | |a published: Print-Electronic | ||
500 | |a Citation Status MEDLINE | ||
520 | |a © 2022. The Author(s). | ||
520 | |a Neuropsychiatric disorders classically lack defining brain pathologies, but recent work has demonstrated dysregulation at the molecular level, characterized by transcriptomic and epigenetic alterations1-3. In autism spectrum disorder (ASD), this molecular pathology involves the upregulation of microglial, astrocyte and neural-immune genes, the downregulation of synaptic genes, and attenuation of gene-expression gradients in cortex1,2,4-6. However, whether these changes are limited to cortical association regions or are more widespread remains unknown. To address this issue, we performed RNA-sequencing analysis of 725 brain samples spanning 11 cortical areas from 112 post-mortem samples from individuals with ASD and neurotypical controls. We find widespread transcriptomic changes across the cortex in ASD, exhibiting an anterior-to-posterior gradient, with the greatest differences in primary visual cortex, coincident with an attenuation of the typical transcriptomic differences between cortical regions. Single-nucleus RNA-sequencing and methylation profiling demonstrate that this robust molecular signature reflects changes in cell-type-specific gene expression, particularly affecting excitatory neurons and glia. Both rare and common ASD-associated genetic variation converge within a downregulated co-expression module involving synaptic signalling, and common variation alone is enriched within a module of upregulated protein chaperone genes. These results highlight widespread molecular changes across the cerebral cortex in ASD, extending beyond association cortex to broadly involve primary sensory regions | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Research Support, N.I.H., Extramural | |
650 | 4 | |a Research Support, Non-U.S. Gov't | |
650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
650 | 7 | |a RNA |2 NLM | |
650 | 7 | |a 63231-63-0 |2 NLM | |
700 | 1 | |a Haney, Jillian R |e verfasserin |4 aut | |
700 | 1 | |a Wamsley, Brie |e verfasserin |4 aut | |
700 | 1 | |a Yap, Chloe X |e verfasserin |4 aut | |
700 | 1 | |a Parhami, Sepideh |e verfasserin |4 aut | |
700 | 1 | |a Emani, Prashant S |e verfasserin |4 aut | |
700 | 1 | |a Chang, Nathan |e verfasserin |4 aut | |
700 | 1 | |a Chen, George T |e verfasserin |4 aut | |
700 | 1 | |a Hoftman, Gil D |e verfasserin |4 aut | |
700 | 1 | |a de Alba, Diego |e verfasserin |4 aut | |
700 | 1 | |a Ramaswami, Gokul |e verfasserin |4 aut | |
700 | 1 | |a Hartl, Christopher L |e verfasserin |4 aut | |
700 | 1 | |a Bhattacharya, Arjun |e verfasserin |4 aut | |
700 | 1 | |a Luo, Chongyuan |e verfasserin |4 aut | |
700 | 1 | |a Jin, Ting |e verfasserin |4 aut | |
700 | 1 | |a Wang, Daifeng |e verfasserin |4 aut | |
700 | 1 | |a Kawaguchi, Riki |e verfasserin |4 aut | |
700 | 1 | |a Quintero, Diana |e verfasserin |4 aut | |
700 | 1 | |a Ou, Jing |e verfasserin |4 aut | |
700 | 1 | |a Wu, Ye Emily |e verfasserin |4 aut | |
700 | 1 | |a Parikshak, Neelroop N |e verfasserin |4 aut | |
700 | 1 | |a Swarup, Vivek |e verfasserin |4 aut | |
700 | 1 | |a Belgard, T Grant |e verfasserin |4 aut | |
700 | 1 | |a Gerstein, Mark |e verfasserin |4 aut | |
700 | 1 | |a Pasaniuc, Bogdan |e verfasserin |4 aut | |
700 | 1 | |a Geschwind, Daniel H |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Nature |d 1945 |g 611(2022), 7936 vom: 01. Nov., Seite 532-539 |w (DE-627)NLM000008257 |x 1476-4687 |7 nnns |
773 | 1 | 8 | |g volume:611 |g year:2022 |g number:7936 |g day:01 |g month:11 |g pages:532-539 |
856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41586-022-05377-7 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 611 |j 2022 |e 7936 |b 01 |c 11 |h 532-539 |