Integrative functional genomic analysis of human brain development and neuropsychiatric risks
Li M., Santpere G., Imamura Kawasawa Y., Evgrafov OV., Gulden FO., Pochareddy S., Sunkin SM., Li Z., Shin Y., Zhu Y., Sousa AMM., Werling DM., Kitchen RR., Kang HJ., Pletikos M., Choi J., Muchnik S., Xu X., Wang D., Lorente-Galdos B., Liu S., Giusti-Rodríguez P., Won H., de Leeuw CA., Pardiñas AF., Hu M., Jin F., Li Y., Owen MJ., O’Donovan MC., Walters JTR., Posthuma D., Reimers MA., Levitt P., Weinberger DR., Hyde TM., Kleinman JE., Geschwind DH., Hawrylycz MJ., State MW., Sanders SJ., Sullivan PF., Gerstein MB., Lein ES., Knowles JA., Sestan N., Willsey AJ., Oldre A., Szafer A., Camarena A., Cherskov A., Charney AW., Abyzov A., Kozlenkov A., Safi A., Jones AR., Ashley-Koch AE., Ebbert A., Price AJ., Sekijima A., Kefi A., Bernard A., Amiri A., Sboner A., Clark A., Jaffe AE., Tebbenkamp ATN., Sodt AJ., Guillozet-Bongaarts AL., Nairn AC., Carey A., Huttner A., Chervenak A., Szekely A., Shieh AW., Harmanci A., Lipska BK., Carlyle BC., Gregor BW., Kassim BS., Sheppard B., Bichsel C., Hahn C-G., Lee C-K., Chen C., Kuan CL., Dang C., Lau C., Cuhaciyan C., Armoskus C., Mason CE., Liu C., Slaughterbeck CR., Bennet C., Pinto D., Polioudakis D., Franjic D., Miller DJ., Bertagnolli D., Lewis DA., Feng D., Sandman D., Clarke D., Williams D., DelValle D., Fitzgerald D., Shen EH., Flatow E., Zharovsky E., Burke EE., Olson E., Fulfs E., Mattei E., Hadjimichael E., Deelman E., Navarro FCP., Wu F., Lee F., Cheng F., Goes FS., Vaccarino FM., Liu F., Hoffman GE., Gürsoy G., Gee G., Mehta G., Coppola G., Giase G., Sedmak G., Johnson GD., Wray GA., Crawford GE., Gu G., van Bakel H., Witt H., Yoon HJ., Pratt H., Zhao H., Glass IA., Huey J., Arnold J., Noonan JP., Bendl J., Jochim JM., Goldy J., Herstein J., Wiseman JR., Miller JA., Mariani J., Stoll J., Moore J., Szatkiewicz J., Leng J., Zhang J., Parente J., Rozowsky J., Fullard JF., Hohmann JG., Morris J., Phillips JW., Warrell J., Shin JH., An J-Y., Belmont J., Nyhus J., Pendergraft J., Bryois J., Roll K., Grennan KS., Aiona K., White KP., Aldinger KA., Smith KA., Girdhar K., Brouner K., Mangravite LM., Brown L., Collado-Torres L., Cheng L., Gourley L., Song L., Ubieta LDLT., Habegger L., Ng L., Hauberg ME., Onorati M., Webster MJ., Kundakovic M., Skarica M., Reimers M., Johnson MB., Chen MM., Garrett ME., Sarreal M., Reding M., Gu M., Peters MA., Fisher M., Gandal MJ., Purcaro M., Smith M., Brown M., Shibata M., Brown M., Xu M., Yang M., Ray M., Shapovalova NV., Francoeur N., Sjoquist N., Mastan N., Kaur N., Parikshak N., Mosqueda NF., Ngo N-K., Dee N., Ivanov NA., Devillers O., Roussos P., Parker PD., Manser P., Wohnoutka P., Farnham PJ., Zandi P., Emani PS., Dalley RA., Mayani R., Tao R., Gittin R., Straub RE., Lifton RP., Jacobov R., Howard RE., Park RB., Dai R., Abramowicz S., Akbarian S., Schreiner S., Ma S., Parry SE., Shapouri S., Weissman S., Caldejon S., Mane S., Ding S-L., Scuderi S., Dracheva S., Butler S., Lisgo SN., Rhie SK., Lindsay S., Datta S., Souaiaia T., Roychowdhury T., Gomez T., Naluai-Cecchini T., Beach TG., Goodman T., Gao T., Dolbeare TA., Fliss T., Reddy TE., Chen T., Hyde TM., Brunetti T., Lemon TA., Desta T., Borrman T., Haroutunian V., Spitsyna VN., Swarup V., Shi X., Jiang Y., Xia Y., Chen Y-H., Jiang Y., Wang Y., Chae Y., Yang YT., Kim Y., Riley ZL., Krsnik Z., Deng Z., Weng Z., Lin Z., Li Z.
INTRODUCTIONThe brain is responsible for cognition, behavior, and much of what makes us uniquely human. The development of the brain is a highly complex process, and this process is reliant on precise regulation of molecular and cellular events grounded in the spatiotemporal regulation of the transcriptome. Disruption of this regulation can lead to neuropsychiatric disorders.RATIONALEThe regulatory, epigenomic, and transcriptomic features of the human brain have not been comprehensively compiled across time, regions, or cell types. Understanding the etiology of neuropsychiatric disorders requires knowledge not just of endpoint differences between healthy and diseased brains but also of the developmental and cellular contexts in which these differences arise. Moreover, an emerging body of research indicates that many aspects of the development and physiology of the human brain are not well recapitulated in model organisms, and therefore it is necessary that neuropsychiatric disorders be understood in the broader context of the developing and adult human brain.RESULTSHere we describe the generation and analysis of a variety of genomic data modalities at the tissue and single-cell levels, including transcriptome, DNA methylation, and histone modifications across multiple brain regions ranging in age from embryonic development through adulthood. We observed a widespread transcriptomic transition beginning during late fetal development and consisting of sharply decreased regional differences. This reduction coincided with increases in the transcriptional signatures of mature neurons and the expression of genes associated with dendrite development, synapse development, and neuronal activity, all of which were temporally synchronous across neocortical areas, as well as myelination and oligodendrocytes, which were asynchronous. Moreover, genes includingMEF2C,SATB2, andTCF4,with genetic associations to multiple brain-related traits and disorders, converged in a small number of modules exhibiting spatial or spatiotemporal specificity.CONCLUSIONWe generated and applied our dataset to document transcriptomic and epigenetic changes across human development and then related those changes to major neuropsychiatric disorders. These data allowed us to identify genes, cell types, gene coexpression modules, and spatiotemporal loci where disease risk might converge, demonstrating the utility of the dataset and providing new insights into human development and disease.Spatiotemporal dynamics of human brain development and neuropsychiatric risks.Human brain development begins during embryonic development and continues through adulthood (top). Integrating data modalities (bottom left) revealed age- and cell type–specific properties and global patterns of transcriptional dynamics, including a late fetal transition (bottom middle). We related the variation in gene expression (brown, high; purple, low) to regulatory elements in the fetal and adult brains, cell type–specific signatures, and genetic loci associated with neuropsychiatric disorders (bottom right; gray circles indicate enrichment for corresponding features among module genes). Relationships depicted in this panel do not correspond to specific observations. CBC, cerebellar cortex; STR, striatum; HIP, hippocampus; MD, mediodorsal nucleus of thalamus; AMY, amygdala.