Exploiting aberrant mRNA expression in autism for gene discovery and diagnosis

Human Genetics

Volumn 135, Issue 7, 2016, Pages 797-811

  Guan, Jinting ^a,b   Yang, Ence ^b,c   Yang, Jizhou ^b   Zeng, Yong ^a,b   Ji, Guoli ^a   Cai, James J ^b,d  

^a XIAMEN UNIVERSITY   (China)

^b TEXAS A AND M UNIVERSITY   (United States)

^c PEKING UNIVERSITY HEALTH SCIENCE CENTER   (China)

^d TEXAS A AND M UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CHEMOKINE RECEPTOR CX3CR1; FIBROBLAST GROWTH FACTOR RECEPTOR 2; HISTAMINE; HISTIDINE DECARBOXYLASE; MAMMALIAN TARGET OF RAPAMYCIN; MESSENGER RNA; SNARE PROTEIN; SYNAPSIN II;

ARTICLE; AUTISM; BRAIN TISSUE; CONTROLLED STUDY; CPLX2 GENE; DISPERSION; EARLY DIAGNOSIS; FRONTAL CORTEX; GENE; GENE EXPRESSION; GENETIC HETEROGENEITY; HUMAN; HUMAN TISSUE; IMMUNE RESPONSE; PRIORITY JOURNAL; RNA SEQUENCE; BRAIN; FEMALE; GENE EXPRESSION PROFILING; GENE EXPRESSION REGULATION; GENE REGULATORY NETWORK; GENETIC ASSOCIATION STUDY; GENETIC PREDISPOSITION; GENETICS; MALE; METABOLISM; PATHOLOGY; SINGLE NUCLEOTIDE POLYMORPHISM;

AUTISM SPECTRUM DISORDER; BRAIN; FEMALE; GENE EXPRESSION PROFILING; GENE EXPRESSION REGULATION; GENE REGULATORY NETWORKS; GENETIC ASSOCIATION STUDIES; GENETIC PREDISPOSITION TO DISEASE; HUMANS; MALE; POLYMORPHISM, SINGLE NUCLEOTIDE;

EID: 84964650690     PISSN: 03406717     EISSN: 14321203     Source Type: Journal    
DOI: 10.1007/s00439-016-1673-7     Document Type: Article

References (89)

1. Abrahams BS, Geschwind DH (2008) Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet 9:341–355. doi:10.1038/nrg2346
2. Baribeau DA, Anagnostou E (2015) Oxytocin and vasopressin: linking pituitary neuropeptides and their receptors to social neurocircuits. Front Neurosci 9:335. doi:10.3389/fnins.2015.00335
3. Belmonte MK, Cook EH Jr, Anderson GM, Rubenstein JL, Greenough WT, Beckel-Mitchener A, Courchesne E, Boulanger LM, Powell SB, Levitt PR, Perry EK, Jiang YH, DeLorey TM, Tierney E (2004) Autism as a disorder of neural information processing: directions for research and targets for therapy. Mol Psychiatry 9:646–663. doi:10.1038/sj.mp.4001499
4. Benfenati F, Valtorta F, Bahler M, Greengard P (1989) Synapsin I, a neuron-specific phosphoprotein interacting with small synaptic vesicles and F-actin. Cell Biol Int Rep 13:1007–1021
5. Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate—a practical and powerful approach to multiple testing. J R Stat Soc Ser B Methodol 57:289–300. doi:10.2307/2346101
6. Butler MG, Rafi SK, Hossain W, Stephan DA, Manzardo AM (2015) Whole exome sequencing in females with autism implicates novel and candidate genes. Int J Mol Sci 16:1312–1335. doi:10.3390/ijms16011312
7. Cai JJ, Borenstein E, Petrov DA (2010) Broker genes in human disease. Genome Biol Evol 2:815–825. doi:10.1093/gbe/evq064
8. Cesca F, Baldelli P, Valtorta F, Benfenati F (2010) The synapsins: key actors of synapse function and plasticity. Prog Neurobiol 91:313–348. doi:10.1016/j.pneurobio.2010.04.006
9. Chow ML, Pramparo T, Winn ME, Barnes CC, Li HR, Weiss L, Fan JB, Murray S, April C, Belinson H, Fu XD, Wynshaw-Boris A, Schork NJ, Courchesne E (2012) Age-dependent brain gene expression and copy number anomalies in autism suggest distinct pathological processes at young versus mature ages. PLoS Genet 8:e1002592. doi:10.1371/journal.pgen.1002592
10. Clarke RA, Lee S, Eapen V (2012) Pathogenetic model for Tourette syndrome delineates overlap with related neurodevelopmental disorders including autism. Transl Psychiatry 2:e158. doi:10.1038/tp.2012.75
11. Cookson W, Liang L, Abecasis G, Moffatt M, Lathrop M (2009) Mapping complex disease traits with global gene expression. Nat Rev Genet 10:184–194. doi:10.1038/nrg2537
12. Corradi A, Fadda M, Piton A, Patry L, Marte A, Rossi P, Cadieux-Dion M, Gauthier J, Lapointe L, Mottron L, Valtorta F, Rouleau GA, Fassio A, Benfenati F, Cossette P (2014) SYN2 is an autism predisposing gene: loss-of-function mutations alter synaptic vesicle cycling and axon outgrowth. Hum Mol Genet 23:90–103. doi:10.1093/hmg/ddt401
13. Croft D, Mundo AF, Haw R, Milacic M, Weiser J, Wu G, Caudy M, Garapati P, Gillespie M, Kamdar MR, Jassal B, Jupe S, Matthews L, May B, Palatnik S, Rothfels K, Shamovsky V, Song H, Williams M, Birney E, Hermjakob H, Stein L, D’Eustachio P (2014) The Reactome pathway knowledgebase. Nucleic Acids Res 42:D472–D477. doi:10.1093/nar/gkt1102
14. De Rubeis S, Pasciuto E, Li KW, Fernandez E, Di Marino D, Buzzi A, Ostroff LE, Klann E, Zwartkruis FJ, Komiyama NH, Grant SG, Poujol C, Choquet D, Achsel T, Posthuma D, Smit AB, Bagni C (2013) CYFIP1 coordinates mRNA translation and cytoskeleton remodeling to ensure proper dendritic spine formation. Neuron 79:1169–1182. doi:10.1016/j.neuron.2013.06.039
15. De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, Kou Y, Liu L, Fromer M, Walker S, Singh T, Klei L, Kosmicki J, Shih-Chen F, Aleksic B, Biscaldi M, Bolton PF, Brownfeld JM, Cai J, Campbell NG, Carracedo A, Chahrour MH, Chiocchetti AG, Coon H, Crawford EL, Curran SR, Dawson G, Duketis E, Fernandez BA, Gallagher L, Geller E, Guter SJ, Hill RS, Ionita-Laza J, Jimenz Gonzalez P, Kilpinen H, Klauck SM, Kolevzon A, Lee I, Lei I, Lei J, Lehtimaki T, Lin CF, Ma’ayan A, Marshall CR, McInnes AL, Neale B, Owen MJ, Ozaki N, Parellada M, Parr JR, Purcell S, Puura K, Rajagopalan D, Rehnstrom K, Reichenberg A, Sabo A, Sachse M, Sanders SJ, Schafer C, Schulte-Ruther M, Skuse D, Stevens C, Szatmari P, Tammimies K, Valladares O, Voran A, Li-San W, Weiss LA, Willsey AJ, Yu TW, Yuen RK, DDD Study, Homozygosity Mapping Collaborative for Autism, UK10K Consortium, Cook EH, Freitag CM, Gill M, Hultman CM, Lehner T, Palotie A, Schellenberg GD, Sklar P, State MW, Sutcliffe JS, Walsh CA, Scherer SW, Zwick ME, Barett JC, Cutler DJ, Roeder K, Devlin B, Daly MJ, Buxbaum JD (2014) Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515:209–215. doi:10.1038/nature13772
16. Devlin B, Scherer SW (2012) Genetic architecture in autism spectrum disorder. Curr Opin Genet Dev 22:229–237. doi:10.1016/j.gde.2012.03.002
17. Dey SS, Foley JE, Limsirichai P, Schaffer DV, Arkin AP (2015) Orthogonal control of expression mean and variance by epigenetic features at different genomic loci. Mol Syst Biol 11:806. doi:10.15252/msb.20145704
18. Dinwiddie DL, Soden SE, Saunders CJ, Miller NA, Farrow EG, Smith LD, Kingsmore SF (2013) De novo frameshift mutation in ASXL3 in a patient with global developmental delay, microcephaly, and craniofacial anomalies. BMC Med Genomics 6:32. doi:10.1186/1755-8794-6-32
19. Ecker S, Pancaldi V, Rico D, Valencia A (2015) Higher gene expression variability in the more aggressive subtype of chronic lymphocytic leukemia. Genome Med 7:8. doi:10.1186/s13073-014-0125-z
20. Elsabbagh M, Johnson MH (2010) Getting answers from babies about autism. Trends Cogn Sci 14:81–87. doi:10.1016/j.tics.2009.12.005
21. Ercan-Sencicek AG, Stillman AA, Ghosh AK, Bilguvar K, O’Roak BJ, Mason CE, Abbott T, Gupta A, King RA, Pauls DL, Tischfield JA, Heiman GA, Singer HS, Gilbert DL, Hoekstra PJ, Morgan TM, Loring E, Yasuno K, Fernandez T, Sanders S, Louvi A, Cho JH, Mane S, Colangelo CM, Biederer T, Lifton RP, Gunel M, State MW (2010) l-Histidine decarboxylase and Tourette’s syndrome. N Engl J Med 362:1901–1908. doi:10.1056/NEJMoa0907006
22. Fatemi SH, Folsom TD, Reutiman TJ, Sidwell RW (2008) Viral regulation of aquaporin 4, connexin 43, microcephalin and nucleolin. Schizophr Res 98:163–177. doi:10.1016/j.schres.2007.09.031
23. Flint J, Timpson N, Munafo M (2014) Assessing the utility of intermediate phenotypes for genetic mapping of psychiatric disease. Trends Neurosci 37:733–741. doi:10.1016/j.tins.2014.08.007
24. Frye RE, Huffman LC, Elliott GR (2010) Tetrahydrobiopterin as a novel therapeutic intervention for autism. Neurotherapeutics 7:241–249. doi:10.1016/j.nurt.2010.05.004
25. Garbett K, Ebert PJ, Mitchell A, Lintas C, Manzi B, Mirnics K, Persico AM (2008) Immune transcriptome alterations in the temporal cortex of subjects with autism. Neurobiol Dis 30:303–311. doi:10.1016/j.nbd.2008.01.012
26. Gaugler T, Klei L, Sanders SJ, Bodea CA, Goldberg AP, Lee AB, Mahajan M, Manaa D, Pawitan Y, Reichert J, Ripke S, Sandin S, Sklar P, Svantesson O, Reichenberg A, Hultman CM, Devlin B, Roeder K, Buxbaum JD (2014) Most genetic risk for autism resides with common variation. Nat Genet 46:881–885. doi:10.1038/ng.3039
27. Geschwind DH (2008) Autism: many genes, common pathways? Cell 135:391–395. doi:10.1016/j.cell.2008.10.016
28. Geschwind DH (2011) Genetics of autism spectrum disorders. Trends Cogn Sci 15:409–416. doi:10.1016/j.tics.2011.07.003
29. Geschwind DH, State MW (2015) Gene hunting in autism spectrum disorder: on the path to precision medicine. Lancet Neurol 14:1109–1120. doi:10.1016/S1474-4422(15)00044-7
30. Glessner JT, Wang K, Cai G, Korvatska O, Kim CE, Wood S, Zhang H, Estes A, Brune CW, Bradfield JP, Imielinski M, Frackelton EC, Reichert J, Crawford EL, Munson J, Sleiman PM, Chiavacci R, Annaiah K, Thomas K, Hou C, Glaberson W, Flory J, Otieno F, Garris M, Soorya L, Klei L, Piven J, Meyer KJ, Anagnostou E, Sakurai T, Game RM, Rudd DS, Zurawiecki D, McDougle CJ, Davis LK, Miller J, Posey DJ, Michaels S, Kolevzon A, Silverman JM, Bernier R, Levy SE, Schultz RT, Dawson G, Owley T, McMahon WM, Wassink TH, Sweeney JA, Nurnberger JI, Coon H, Sutcliffe JS, Minshew NJ, Grant SF, Bucan M, Cook EH, Buxbaum JD, Devlin B, Schellenberg GD, Hakonarson H (2009) Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459:569–573. doi:10.1038/nature07953
31. Guglielmi L, Servettini I, Caramia M, Catacuzzeno L, Franciolini F, D’Adamo MC, Pessia M (2015) Update on the implication of potassium channels in autism: K(+) channelautism spectrum disorder. Front Cell Neurosci 9:34. doi:10.3389/fncel.2015.00034
32. Gupta S, Ellis SE, Ashar FN, Moes A, Bader JS, Zhan J, West AB, Arking DE (2014) Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism. Nat Commun 5:5748. doi:10.1038/ncomms6748
33. Hansen KD, Irizarry RA, Wu Z (2012) Removing technical variability in RNA-seq data using conditional quantile normalization. Biostatistics 13:204–216. doi:10.1093/biostatistics/kxr054
34. Heinzen EL, Ge D, Cronin KD, Maia JM, Shianna KV, Gabriel WN, Welsh-Bohmer KA, Hulette CM, Denny TN, Goldstein DB (2008) Tissue-specific genetic control of splicing: implications for the study of complex traits. PLoS Biol 6:e1. doi:10.1371/journal.pbio.1000001
35. Hormozdiari F, Penn O, Borenstein E, Eichler EE (2015) The discovery of integrated gene networks for autism and related disorders. Genome Res 25:142–154. doi:10.1101/gr.178855.114
36. Hulse AM, Cai JJ (2013) Genetic variants contribute to gene expression variability in humans. Genetics 193:95–108. doi:10.1534/genetics.112.146779
37. Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I, Rosenbaum J, Yamrom B, Lee YH, Narzisi G, Leotta A, Kendall J, Grabowska E, Ma B, Marks S, Rodgers L, Stepansky A, Troge J, Andrews P, Bekritsky M, Pradhan K, Ghiban E, Kramer M, Parla J, Demeter R, Fulton LL, Fulton RS, Magrini VJ, Ye K, Darnell JC, Darnell RB, Mardis ER, Wilson RK, Schatz MC, McCombie WR, Wigler M (2012) De novo gene disruptions in children on the autistic spectrum. Neuron 74:285–299. doi:10.1016/j.neuron.2012.04.009
38. Iossifov I, O’Roak BJ, Sanders SJ, Ronemus M, Krumm N, Levy D, Stessman HA, Witherspoon KT, Vives L, Patterson KE, Smith JD, Paeper B, Nickerson DA, Dea J, Dong S, Gonzalez LE, Mandell JD, Mane SM, Murtha MT, Sullivan CA, Walker MF, Waqar Z, Wei L, Willsey AJ, Yamrom B, Lee YH, Grabowska E, Dalkic E, Wang Z, Marks S, Andrews P, Leotta A, Kendall J, Hakker I, Rosenbaum J, Ma B, Rodgers L, Troge J, Narzisi G, Yoon S, Schatz MC, Ye K, McCombie WR, Shendure J, Eichler EE, State MW, Wigler M (2014) The contribution of de novo coding mutations to autism spectrum disorder. Nature 515:216–221. doi:10.1038/nature13908
39. Jalbrzikowski M, Lazaro MT, Gao F, Huang A, Chow C, Geschwind DH, Coppola G, Bearden CE (2015) Transcriptome profiling of peripheral blood in 22q11.2 deletion syndrome reveals functional pathways related to psychosis and autism spectrum disorder. PLoS One 10:e0132542. doi:10.1371/journal.pone.0132542
40. Klaiman C, Huffman L, Masaki L, Elliott GR (2013) Tetrahydrobiopterin as a treatment for autism spectrum disorders: a double-blind, placebo-controlled trial. J Child Adolesc Psychopharmacol 23:320–328. doi:10.1089/cap.2012.0127
41. Klei L, Sanders SJ, Murtha MT, Hus V, Lowe JK, Willsey AJ, Moreno-De-Luca D, Yu TW, Fombonne E, Geschwind D, Grice DE, Ledbetter DH, Lord C, Mane SM, Martin CL, Martin DM, Morrow EM, Walsh CA, Melhem NM, Chaste P, Sutcliffe JS, State MW, Cook EH Jr, Roeder K, Devlin B (2012) Common genetic variants, acting additively, are a major source of risk for autism. Mol Autism 3:9. doi:10.1186/2040-2392-3-9
42. Kong SW, Collins CD, Shimizu-Motohashi Y, Holm IA, Campbell MG, Lee IH, Brewster SJ, Hanson E, Harris HK, Lowe KR, Saada A, Mora A, Madison K, Hundley R, Egan J, McCarthy J, Eran A, Galdzicki M, Rappaport L, Kunkel LM, Kohane IS (2012) Characteristics and predictive value of blood transcriptome signature in males with autism spectrum disorders. PLoS One 7:e49475. doi:10.1371/journal.pone.0049475
43. Konganti K, Wang G, Yang E, Cai JJ (2013) SBEToolbox: a Matlab toolbox for biological network analysis. Evol Bioinform Online 9:355–362. doi:10.4137/EBO.S12012
44. Langfelder P, Horvath S (2008) WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics 9:559. doi:10.1186/1471-2105-9-559
45. Langfelder P, Luo R, Oldham MC, Horvath S (2011) Is my network module preserved and reproducible? PLoS Comput Biol 7:e1001057. doi:10.1371/journal.pcbi.1001057
46. Lazaro MT, Golshani P (2015) The utility of rodent models of autism spectrum disorders. Curr Opin Neurol 28:103–109. doi:10.1097/WCO.0000000000000183
47. Lee HJ, Song JY, Kim JW, Jin SY, Hong MS, Park JK, Chung JH, Shibata H, Fukumaki Y (2005) Association study of polymorphisms in synaptic vesicle-associated genes, SYN2 and CPLX2, with schizophrenia. Behav Brain Funct 1:15. doi:10.1186/1744-9081-1-15
48. Lee H, Lin MC, Kornblum HI, Papazian DM, Nelson SF (2014) Exome sequencing identifies de novo gain of function missense mutation in KCND2 in identical twins with autism and seizures that slows potassium channel inactivation. Hum Mol Genet 23:3481–3489. doi:10.1093/hmg/ddu056
49. Li J, Liu Y, Kim T, Min R, Zhang Z (2010) Gene expression variability within and between human populations and implications toward disease susceptibility. PLoS Comput Biol 6:e1000910. doi:10.1371/journal.pcbi.1000910
50. Li J, Shi M, Ma Z, Zhao S, Euskirchen G, Ziskin J, Urban A, Hallmayer J, Snyder M (2014) Integrated systems analysis reveals a molecular network underlying autism spectrum disorders. Mol Syst Biol 10:774. doi:10.15252/msb.20145487
51. Liberzon A, Subramanian A, Pinchback R, Thorvaldsdottir H, Tamayo P, Mesirov JP (2011) Molecular signatures database (MSigDB) 3.0. Bioinformatics 27:1739–1740. doi:10.1093/bioinformatics/btr260
52. Lim MM, Bielsky IF, Young LJ (2005) Neuropeptides and the social brain: potential rodent models of autism. Int J Dev Neurosci 23:235–243. doi:10.1016/j.ijdevneu.2004.05.006
53. Lionel AC, Crosbie J, Barbosa N, Goodale T, Thiruvahindrapuram B, Rickaby J, Gazzellone M, Carson AR, Howe JL, Wang Z, Wei J, Stewart AF, Roberts R, McPherson R, Fiebig A, Franke A, Schreiber S, Zwaigenbaum L, Fernandez BA, Roberts W, Arnold PD, Szatmari P, Marshall CR, Schachar R, Scherer SW (2011) Rare copy number variation discovery and cross-disorder comparisons identify risk genes for ADHD. Sci Transl Med 3:95ra75. doi:10.1126/scitranslmed.3002464
54. Mahalanobis PC (1936) On the generalised distance in statistics. Proc Natl Inst Sci India 2:49–55. doi:citeulike-article-id:4155812
55. Mar JC, Matigian NA, Mackay-Sim A, Mellick GD, Sue CM, Silburn PA, McGrath JJ, Quackenbush J, Wells CA (2011) Variance of gene expression identifies altered network constraints in neurological disease. PLoS Genet 7:e1002207. doi:10.1371/journal.pgen.1002207
56. Neale BM, Kou Y, Liu L, Ma’ayan A, Samocha KE, Sabo A, Lin CF, Stevens C, Wang LS, Makarov V, Polak P, Yoon S, Maguire J, Crawford EL, Campbell NG, Geller ET, Valladares O, Schafer C, Liu H, Zhao T, Cai G, Lihm J, Dannenfelser R, Jabado O, Peralta Z, Nagaswamy U, Muzny D, Reid JG, Newsham I, Wu Y, Lewis L, Han Y, Voight BF, Lim E, Rossin E, Kirby A, Flannick J, Fromer M, Shakir K, Fennell T, Garimella K, Banks E, Poplin R, Gabriel S, DePristo M, Wimbish JR, Boone BE, Levy SE, Betancur C, Sunyaev S, Boerwinkle E, Buxbaum JD, Cook EH Jr, Devlin B, Gibbs RA, Roeder K, Schellenberg GD, Sutcliffe JS, Daly MJ (2012) Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485:242–245. doi:10.1038/nature11011
57. O’Roak BJ, Vives L, Fu W, Egertson JD, Stanaway IB, Phelps IG, Carvill G, Kumar A, Lee C, Ankenman K, Munson J, Hiatt JB, Turner EH, Levy R, O’Day DR, Krumm N, Coe BP, Martin BK, Borenstein E, Nickerson DA, Mefford HC, Doherty D, Akey JM, Bernier R, Eichler EE, Shendure J (2012a) Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338:1619–1622. doi:10.1126/science.1227764
58. O’Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, Levy R, Ko A, Lee C, Smith JD, Turner EH, Stanaway IB, Vernot B, Malig M, Baker C, Reilly B, Akey JM, Borenstein E, Rieder MJ, Nickerson DA, Bernier R, Shendure J, Eichler EE (2012b) Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485:246–250. doi:10.1038/nature10989
59. Parikshak NN, Luo R, Zhang A, Won H, Lowe JK, Chandran V, Horvath S, Geschwind DH (2013) Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism. Cell 155:1008–1021. doi:10.1016/j.cell.2013.10.031
60. Persico AM, Bourgeron T (2006) Searching for ways out of the autism maze: genetic, epigenetic and environmental clues. Trends Neurosci 29:349–358. doi:10.1016/j.tins.2006.05.010
61. Pettem KL, Yokomaku D, Takahashi H, Ge Y, Craig AM (2013) Interaction between autism-linked MDGAs and neuroligins suppresses inhibitory synapse development. J Cell Biol 200:321–336. doi:10.1083/jcb.201206028
62. Pinto D, Delaby E, Merico D, Barbosa M, Merikangas A, Klei L, Thiruvahindrapuram B, Xu X, Ziman R, Wang Z, Vorstman JA, Thompson A, Regan R, Pilorge M, Pellecchia G, Pagnamenta AT, Oliveira B, Marshall CR, Magalhaes TR, Lowe JK, Howe JL, Griswold AJ, Gilbert J, Duketis E, Dombroski BA, De Jonge MV, Cuccaro M, Crawford EL, Correia CT, Conroy J, Conceicao IC, Chiocchetti AG, Casey JP, Cai G, Cabrol C, Bolshakova N, Bacchelli E, Anney R, Gallinger S, Cotterchio M, Casey G, Zwaigenbaum L, Wittemeyer K, Wing K, Wallace S, van Engeland H, Tryfon A, Thomson S, Soorya L, Roge B, Roberts W, Poustka F, Mouga S, Minshew N, McInnes LA, McGrew SG, Lord C, Leboyer M, Le Couteur AS, Kolevzon A, Jimenez Gonzalez P, Jacob S, Holt R, Guter S, Green J, Green A, Gillberg C, Fernandez BA, Duque F, Delorme R, Dawson G, Chaste P, Cafe C, Brennan S, Bourgeron T, Bolton PF, Bolte S, Bernier R, Baird G, Bailey AJ, Anagnostou E, Almeida J, Wijsman EM, Vieland VJ, Vicente AM, Schellenberg GD, Pericak-Vance M, Paterson AD, Parr JR, Oliveira G, Nurnberger JI, Monaco AP, Maestrini E, Klauck SM, Hakonarson H, Haines JL, Geschwind DH, Freitag CM, Folstein SE, Ennis S et al (2014) Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Am J Hum Genet 94:677–694. doi:10.1016/j.ajhg.2014.03.018
63. Pramparo T, Pierce K, Lombardo MV, Carter Barnes C, Marinero S, Ahrens-Barbeau C, Murray SS, Lopez L, Xu R, Courchesne E (2015) Prediction of autism by translation and immune/inflammation coexpressed genes in toddlers from pediatric community practices. JAMA Psychiatry 72:386–394. doi:10.1001/jamapsychiatry.2014.3008
64. Ramanathan S, Woodroffe A, Flodman PL, Mays LZ, Hanouni M, Modahl CB, Steinberg-Epstein R, Bocian ME, Spence MA, Smith M (2004) A case of autism with an interstitial deletion on 4q leading to hemizygosity for genes encoding for glutamine and glycine neurotransmitter receptor sub-units (AMPA 2, GLRA3, GLRB) and neuropeptide receptors NPY1R, NPY5R. BMC Med Genet 5:10. doi:10.1186/1471-2350-5-10
65. Rousseeuw PJ, Van Driessen K (1999) A fast algorithm for the minimum covariance determinant estimator. Technometrics 41:212–223. doi:10.2307/1270566
66. Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN, Stein JL, Walker MF, Ober GT, Teran NA, Song Y, El-Fishawy P, Murtha RC, Choi M, Overton JD, Bjornson RD, Carriero NJ, Meyer KA, Bilguvar K, Mane SM, Sestan N, Lifton RP, Gunel M, Roeder K, Geschwind DH, Devlin B, State MW (2012) De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485:237–241. doi:10.1038/nature10945
67. Sandin S, Lichtenstein P, Kuja-Halkola R, Larsson H, Hultman CM, Reichenberg A (2014) The familial risk of autism. JAMA 311:1770–1777. doi:10.1001/jama.2014.4144
68. Sawicka K, Zukin RS (2012) Dysregulation of mTOR signaling in neuropsychiatric disorders: therapeutic implications. Neuropsychopharmacology 37:305–306. doi:10.1038/npp.2011.210
69. Schaaf CP, Sabo A, Sakai Y, Crosby J, Muzny D, Hawes A, Lewis L, Akbar H, Varghese R, Boerwinkle E, Gibbs RA, Zoghbi HY (2011) Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders. Hum Mol Genet 20:3366–3375. doi:10.1093/hmg/ddr243
70. Schubert D, Martens GJ, Kolk SM (2015) Molecular underpinnings of prefrontal cortex development in rodents provide insights into the etiology of neurodevelopmental disorders. Mol Psychiatry 20:795–809. doi:10.1038/mp.2014.147
71. Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T, Yamrom B, Yoon S, Krasnitz A, Kendall J, Leotta A, Pai D, Zhang R, Lee YH, Hicks J, Spence SJ, Lee AT, Puura K, Lehtimaki T, Ledbetter D, Gregersen PK, Bregman J, Sutcliffe JS, Jobanputra V, Chung W, Warburton D, King MC, Skuse D, Geschwind DH, Gilliam TC, Ye K, Wigler M (2007) Strong association of de novo copy number mutations with autism. Science 316:445–449. doi:10.1126/science.1138659
72. Smedley D, Haider S, Durinck S, Pandini L, Provero P, Allen J, Arnaiz O, Awedh MH, Baldock R, Barbiera G, Bardou P, Beck T, Blake A, Bonierbale M, Brookes AJ, Bucci G, Buetti I, Burge S, Cabau C, Carlson JW, Chelala C, Chrysostomou C, Cittaro D, Collin O, Cordova R, Cutts RJ, Dassi E, Di Genova A, Djari A, Esposito A, Estrella H, Eyras E, Fernandez-Banet J, Forbes S, Free RC, Fujisawa T, Gadaleta E, Garcia-Manteiga JM, Goodstein D, Gray K, Guerra-Assuncao JA, Haggarty B, Han DJ, Han BW, Harris T, Harshbarger J, Hastings RK, Hayes RD, Hoede C, Hu S, Hu ZL, Hutchins L, Kan Z, Kawaji H, Keliet A, Kerhornou A, Kim S, Kinsella R, Klopp C, Kong L, Lawson D, Lazarevic D, Lee JH, Letellier T, Li CY, Lio P, Liu CJ, Luo J, Maass A, Mariette J, Maurel T, Merella S, Mohamed AM, Moreews F, Nabihoudine I, Ndegwa N, Noirot C, Perez-Llamas C, Primig M, Quattrone A, Quesneville H, Rambaldi D, Reecy J, Riba M, Rosanoff S, Saddiq AA, Salas E, Sallou O, Shepherd R, Simon R, Sperling L, Spooner W, Staines DM, Steinbach D, Stone K, Stupka E, Teague JW, Dayem Ullah AZ, Wang J, Ware D et al (2015) The BioMart community portal: an innovative alternative to large, centralized data repositories. Nucleic Acids Res 43:W589–W598. doi:10.1093/nar/gkv350
73. Somel M, Khaitovich P, Bahn S, Paabo S, Lachmann M (2006) Gene expression becomes heterogeneous with age. Curr Biol 16:R359–R360. doi:10.1016/j.cub.2006.04.024
74. Stegle O, Parts L, Durbin R, Winn J (2010) A Bayesian framework to account for complex non-genetic factors in gene expression levels greatly increases power in eQTL studies. PLoS Comput Biol 6:e1000770. doi:10.1371/journal.pcbi.1000770
75. Stevens HE, Smith KM, Maragnoli ME, Fagel D, Borok E, Shanabrough M, Horvath TL, Vaccarino FM (2010) Fgfr2 is required for the development of the medial prefrontal cortex and its connections with limbic circuits. J Neurosci 30:5590–5602. doi:10.1523/JNEUROSCI.5837-09.2010
76. Tabuchi K, Blundell J, Etherton MR, Hammer RE, Liu X, Powell CM, Sudhof TC (2007) A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science 318:71–76. doi:10.1126/science.1146221
77. Tammimies K, Marshall CR, Walker S, Kaur G, Thiruvahindrapuram B, Lionel AC, Yuen RK, Uddin M, Roberts W, Weksberg R, Woodbury-Smith M, Zwaigenbaum L, Anagnostou E, Wang Z, Wei J, Howe JL, Gazzellone MJ, Lau L, Sung WW, Whitten K, Vardy C, Crosbie V, Tsang B, D’Abate L, Tong WW, Luscombe S, Doyle T, Carter MT, Szatmari P, Stuckless S, Merico D, Stavropoulos DJ, Scherer SW, Fernandez BA (2015) Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder. JAMA 314:895–903. doi:10.1001/jama.2015.10078
78. Tierney E, Bukelis I, Thompson RE, Ahmed K, Aneja A, Kratz L, Kelley RI (2006) Abnormalities of cholesterol metabolism in autism spectrum disorders. Am J Med Genet B Neuropsychiatr Genet 141B:666–668. doi:10.1002/ajmg.b.30368
79. Turner TN, Hormozdiari F, Duyzend MH, McClymont SA, Hook PW, Iossifov I, Raja A, Baker C, Hoekzema K, Stessman HA, Zody MC, Nelson BJ, Huddleston J, Sandstrom R, Smith JD, Hanna D, Swanson JM, Faustman EM, Bamshad MJ, Stamatoyannopoulos J, Nickerson DA, McCallion AS, Darnell R, Eichler EE (2016) Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA. Am J Hum Genet 98:58–74. doi:10.1016/j.ajhg.2015.11.023
80. Verboven S, Hubert M (2005) LIBRA: a MATLAB library for robust analysis. Chemometr Intell Lab Syst 75:127–136. doi:10.1016/j.chemolab.2004.06.003
81. Voineagu I, Wang X, Johnston P, Lowe JK, Tian Y, Horvath S, Mill J, Cantor RM, Blencowe BJ, Geschwind DH (2011) Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 474:380–384. doi:10.1038/nature10110
82. Walsh P, Elsabbagh M, Bolton P, Singh I (2011) In search of biomarkers for autism: scientific, social and ethical challenges. Nat Rev Neurosci 12:603–612. doi:10.1038/nrn3113
83. Wang K, Zhang H, Ma D, Bucan M, Glessner JT, Abrahams BS, Salyakina D, Imielinski M, Bradfield JP, Sleiman PM, Kim CE, Hou C, Frackelton E, Chiavacci R, Takahashi N, Sakurai T, Rappaport E, Lajonchere CM, Munson J, Estes A, Korvatska O, Piven J, Sonnenblick LI, Alvarez Retuerto AI, Herman EI, Dong H, Hutman T, Sigman M, Ozonoff S, Klin A, Owley T, Sweeney JA, Brune CW, Cantor RM, Bernier R, Gilbert JR, Cuccaro ML, McMahon WM, Miller J, State MW, Wassink TH, Coon H, Levy SE, Schultz RT, Nurnberger JI, Haines JL, Sutcliffe JS, Cook EH, Minshew NJ, Buxbaum JD, Dawson G, Grant SF, Geschwind DH, Pericak-Vance MA, Schellenberg GD, Hakonarson H (2009) Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 459:528–533. doi:10.1038/nature07999
84. Wang G, Yang E, Brinkmeyer-Langford CL, Cai JJ (2014) Additive, epistatic, and environmental effects through the lens of expression variability QTL in a twin cohort. Genetics 196:413–425. doi:10.1534/genetics.113.157503
85. Waterhouse L, Gillberg C (2014) Why autism must be taken apart. J Autism Dev Disord 44:1788–1792. doi:10.1007/s10803-013-2030-5
86. Weiss LA, Arking DE, Gene Discovery Project of Johns Hopkins and the Autism Consortium, Daly MJ, Chakravarti A (2009) A genome-wide linkage and association scan reveals novel loci for autism. Nature 461:802–808. doi:10.1038/nature08490
87. Willsey AJ, State MW (2015) Autism spectrum disorders: from genes to neurobiology. Curr Opin Neurobiol 30:92–99. doi:10.1016/j.conb.2014.10.015
88. Willsey AJ, Sanders SJ, Li M, Dong S, Tebbenkamp AT, Muhle RA, Reilly SK, Lin L, Fertuzinhos S, Miller JA, Murtha MT, Bichsel C, Niu W, Cotney J, Ercan-Sencicek AG, Gockley J, Gupta AR, Han W, He X, Hoffman EJ, Klei L, Lei J, Liu W, Liu L, Lu C, Xu X, Zhu Y, Mane SM, Lein ES, Wei L, Noonan JP, Roeder K, Devlin B, Sestan N, State MW (2013) Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. Cell 155:997–1007. doi:10.1016/j.cell.2013.10.020
89. Zeng Y, Wang G, Yang E, Ji G, Brinkmeyer-Langford CL, Cai JJ (2015) Aberrant gene expression in humans. PLoS Genet 11:e1004942. doi:10.1371/journal.pgen.1004942