nach oben

Journal of the Association for Research in Otolaryngology

Erschienen in:

30.11.2023 | Original Article

Genome-Wide Association Study of Chronic Dizziness in the Elderly Identifies Loci Implicating MLLT10, BPTF, LINC01224, and ROS1

verfasst von: Royce Clifford, Daniel Munro, Daniel Dochtermann, Poornima Devineni, Saiju Pyarajan, Francesca Telese, Abraham A. Palmer, Pejman Mohammadi, Rick Friedman, Million Veteran Program

Erschienen in: Journal of the Association for Research in Otolaryngology | Ausgabe 6/2023

Einloggen, um Zugang zu erhalten

Abstract

Purpose

Chronic age-related imbalance is a common cause of falls and subsequent death in the elderly and can arise from dysfunction of the vestibular system, an elegant neuroanatomical group of pathways that mediates human perception of acceleration, gravity, and angular head motion. Studies indicate that 27–46% of the risk of age-related chronic imbalance is genetic; nevertheless, the underlying genes remain unknown.

Methods

The cohort consisted of 50,339 cases and 366,900 controls in the Million Veteran Program. The phenotype comprised cases with two ICD diagnoses of vertigo or dizziness at least 6 months apart, excluding acute or recurrent vertiginous syndromes and other non-vestibular disorders. Genome-wide association studies were performed as individual logistic regressions on European, African American, and Hispanic ancestries followed by trans-ancestry meta-analysis. Downstream analysis included case-case-GWAS, fine mapping, probabilistic colocalization of significant variants and genes with eQTLs, and functional analysis of significant hits.

Results

Two significant loci were identified in Europeans, another in the Hispanic population, and two additional in trans-ancestry meta-analysis, including three novel loci. Fine mapping revealed credible sets of intronic single nucleotide polymorphisms (SNPs) in MLLT10 - a histone methyl transferase cofactor, BPTF - a subunit of a nucleosome remodeling complex implicated in neurodevelopment, and LINC01224 - a proto-oncogene receptor tyrosine kinase.

Conclusion

Despite the difficulties of phenotyping the nature of chronic imbalance, we replicated two loci from previous vertigo GWAS studies and identified three novel loci. Findings suggest candidates for further study and ultimate treatment of this common elderly disorder.

Nur mit Berechtigung zugänglich

Ekvall Hansson E, Magnusson M (2013) Vestibular asymmetry predicts falls among elderly patients with multi- sensory dizziness. BMC Geriatr 13. https://doi.org/10.1186/1471-2318-13-77

Harun A, Semenov YR, Agrawal Y (2015) Vestibular function and activities of daily living: analysis of the 1999 to 2004 National Health and Nutrition Examination Surveys. Gerontol Geriatr Med 1:2333721415607124. https://doi.org/10.1177/2333721415607124. Epub 2015 Sep 21. PMID: 26753170; PMCID: PMC4706363. https://doi.org/10.1177/2333721415607124

Kippenbrock T, Soja ME (2007) Preventing falls in the elderly: interviewing patients who have fallen. Researchers attempt to identify fall-risk factors from the patients’ point of view. Geriatr Nurs 14:205–9

Fernández L, Breinbauer HA, Delano PH (2015) Vertigo and dizziness in the elderly. Front Neurol 6:144PubMedPubMedCentral

Cutson TM (1994) Falls in the elderly. Am Fam Physician 49:149–156PubMed

Teixeira AR, Wender MH, Gonçalves AK, Freitas CDLR, dos Santos AMPV, Soldera CLC (2016) Dizziness, physical exercise, falls, and depression in adults and the elderly. Int Arch Otorhinolaryngol 20:124–131PubMed

Mitchell AJ, Vaze A, Rao S (2009) Clinical diagnosis of depression in primary care: a meta-analysis. Lancet 374:609–619PubMed

Furman JM, Redfern MS (2001) Effect of aging on the otolith-ocular reflex. J Vestib Res 11:91–103PubMed

Baloh RW, Jacobson KM, Socotch TM (1993) The effect of aging on visual-vestibuloocular responses. Exp Brain Res 95:509–516PubMed

10.

Matheson AJ, Darlington CL, Smith PF (1999) Further evidence for age-related deficits in human postural function. J Vestib Res 9:261–264PubMed

11.

Rauch SD, Velazquez-Villaseñor L, Dimitri PS, Merchant SN (2001) Decreasing hair cell counts in aging humans. Ann N Y Acad Sci 942:220–227PubMed

12.

Jang YS, Hwang CH, Shin JY, Bae WY, Kim LS (2006) Age-related changes on the morphology of the otoconia. Laryngoscope 116:996–1001PubMed

13.

Walther LE, Westhofen M (2007) Presbyvertigo-aging of otoconia and vestibular sensory cells. J Vestib Res 17:89–92PubMed

14.

Maes L, Dhooge I, D’haenens W, Bockstael A, Keppler H, Philips B, Swinnen F, Vinck BM (2010) The effect of age on the sinusoidal harmonic acceleration test, pseudorandom rotation test, velocity step test, caloric test, and vestibular-evoked myogenic potential test. Ear Hear 31:84–94

15.

Tanioka H, Tanioka S, Kaga K (2020) Vestibular aging process from 3D physiological imaging of the membranous labyrinth. Published Online First. https://doi.org/10.1038/s41598-020-66520-wCrossRef

16.

Wagner H, Melhus H, Pedersen NL, Michaëlsson K (2009) Heritability of impaired balance: a nationwide cohort study in twins. Osteoporosis Int 20:577–583

17.

El Haber N, Hill KD, Cassano A-MT, Paton LM, Macinnis RJ, Cui JS, Hopper JL, Wark JD (2006) Genetic and environmental influences on variation in balance performance among female twin pairs aged 21–82 years. Am J Epidemiol 164:246–56

18.

Skuladottir ATh, Bjornsdottir G, Nawaz MS, Petersen H, Rognvaldsson S, Moore KHS, Olafsson PI, Magnusson SH, Bjornsdottir A, Sveinsson OA, Sigurdardottir GR, Saevarsdottir S, Ivarsdottir EV, Stefansdottir L, Gunnarsson B, Muhlestein JB, Knowlton KU, Jones DA, Nadauld LD, Hartmann AM, Rujescu D, Strupp M, Walters GB, Thorgeirsson TE, Jonsdottir I, Holm H, Thorleifsson G, Gudbjartsson DF, Sulem P, Stefansson H, Stefansson K (2021) A genome-wide meta-analysis uncovers six sequence variants conferring risk of vertigo. Commun Biol 4:1148PubMedPubMedCentral

19.

Xiao AY, Tan ML, Plana MN, Yadav D, Zamora J, Petrov MS (2018) The use of international classification of diseases codes to identify patients with pancreatitis: a systematic review and meta-analysis of diagnostic accuracy studies. Clin Transl Gastroenterol 9. https://doi.org/10.1038/s41424-018-0060-1

20.

Foley HE, Knight JC, Ploughman M, Asghari S, Audas R (2020) Identifying cases of chronic pain using health administrative data: a validation study. Can J Pain 4:252–267PubMedPubMedCentral

21.

Wassermann A, Finn S, Axer H (2022) Age-associated characteristics of patients with chronic dizziness and vertigo. J Geriatr Psychiatry Neurol 35:580–585PubMed

22.

Müller KJ, Becker-Bense S, Strobl R, Grill E, Dieterich M (2022) Chronic vestibular syndromes in the elderly: presbyvestibulopathy—an isolated clinical entity? Eur J Neurol 29:1825–1835PubMed

23.

Ji L, Zhai S (2018) Aging and the peripheral vestibular system. J Otol 13:138–140PubMedPubMedCentral

24.

Yetiser S (2020) Review of the pathology underlying benign paroxysmal positional vertigo. J Int Med Res 48:300060519892370PubMed

25.

Fang H, Hui Q, Lynch J, Honerlaw J, Assimes TL, Huang J, Vujkovic M, Damrauer SM, Pyarajan S, Gaziano JM, DuVall SL, O’Donnell CJ, Cho K, Chang K-M, Wilson PWF, Tsao PS, Sun YV, Tang H, Gaziano JM, Ramoni R, Breeling J, Chang K-M, Huang G, Muralidhar S, O’Donnell CJ, Tsao PS, Muralidhar S, Moser J, Whitbourne SB, Brewer J V., Concato J, Warren S, Argyres DP, Stephens B, Brophy MT, Humphries DE, Do N, Shayan S, Nguyen X-MT, Pyarajan S, Cho K, Hauser E, Sun Y, Zhao H, Wilson P, McArdle R, Dellitalia L, Harley J, Whittle J, Beckham J, Wells J, Gutierrez S, Gibson G, Kaminsky L, Villareal G, Kinlay S, Xu J, Hamner M, Haddock KS, Bhushan S, Iruvanti P, Godschalk M, Ballas Z, Buford M, Mastorides S, Klein J, Ratcliffe N, Florez H, Swann A, Murdoch M, Sriram P, Yeh SS, Washburn R, Jhala D, Aguayo S, Cohen D, Sharma S, Callaghan J, Oursler KA, Whooley M, Ahuja S, Gutierrez A, Schifman R, Greco J, Rauchman M, Servatius R, Oehlert M, Wallbom A, Fernando R, Morgan T, Stapley T, Sherman S, Anderson G, Sonel E, Boyko E, Meyer L, Gupta S, Fayad J, Hung A, Lichy J, Hurley R, Robey B, Striker R (2019) Harmonizing genetic ancestry and self-identified race/ethnicity in genome-wide association studies. Am J Human Gen 105:763–72

26.

Hunter-Zinck H, Shi Y, Li M, Gorman BR, Ji SG, Sun N, Webster T, Liem A, Hsieh P, Devineni P, Karnam P, Gong X, Radhakrishnan L, Schmidt J, Assimes TL, Huang J, Pan C, Humphries D, Brophy M, Moser J, Muralidhar S, Huang GD, Przygodzki R, Concato J, Gaziano JM, Gelernter J, O’Donnell CJ, Hauser ER, Zhao H, O’Leary TJ, Tsao PS, Pyarajan S (2020) Genotyping array design and data quality control in the Million Veteran Program. Am J Hum Genet 106:535–548PubMedPubMedCentral

27.

Chang CC, Chow CC, Tellier LCAM, Vattikuti S, Purcell SM, Lee JJ (2015) Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience 4:1–16

28.

Zhou W, Nielsen JB, Fritsche LG, Dey R, Maiken E, Wolford BN, Lefaive J, Vandehaar P, Sarah A, Gifford A, Bastarache LA, Wei W, Denny JC, Hveem K, Kang HM, Abecasis GR, Willer CJ (2019) Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies. Nat Genetics 50:1335–1341

29.

Patterson N, Price AL, Reich D (2006) Population structure and eigenanalysis. PLoS Genet 2:190

30.

Mbatchou J, Barnard L, Backman J, Marcketta A, Kosmicki JA, Ziyatdinov A, Benner C, O’Dushlaine C, Barber M, Boutkov B, Habegger L, Ferreira M, Baras A, Reid J, Abecasis G, Maxwell E, Marchini J (2021) Computationally efficient whole-genome regression for quantitative and binary traits. Nat Genet 53. https://doi.org/10.1038/s41588-021-00870-7

31.

Willer CJ, Li Y, Abecasis GR (2010) METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26:2190–2191PubMedPubMedCentral

32.

Bulik-Sullivan BK, Loh P-R, Finucane HK, Ripke S, Yang J, Patterson N, Daly MJ, Price AL, Neale BM (2015) LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat Genet 47:291–295PubMedPubMedCentral

33.

Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, Gliedt TP, Boehnke M, Abecasis GR, Willer CJ (2010) LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26(18):2336–2337. https://doi.org/10.1093/bioinformatics/btq419

34.

Finucane, H, Bulik-Sullivan B, Gusev A, Trynka G, Reshef Y et al (2015) Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat Genet 47:1228–35

35.

Wells HRR, Freidin MB, Zainul Abidin FN et al (2019) GWAS identifies 44 independent associated genomic loci for self-reported adult hearing difficulty in UK Biobank. Am J Hum Genet 105(4):788–802. https://doi.org/10.1016/j.ajhg.2019.09.008CrossRefPubMedPubMedCentral

36.

Clifford RE, Maihofer AX, Stein MB, Ryan AF, Nievergelt CM (2020) Novel risk loci in tinnitus and causal inference with neuropsychiatric disorders among adults of European ancestry. JAMA Otolaryngol Head Neck Surg 146:1015–1025PubMedPubMedCentral

37.

Peyrot WJ, Price AL (2021) Identifying loci with different allele frequencies among cases of eight psychiatric disorders using CC-GWAS. Nat Genet 53:445–454PubMedPubMedCentral

38.

Hukku A, Pividori M, Luca F, Pique-Regi R, Im HK, Wen X (2021) Probabilistic colocalization of genetic variants from complex and molecular traits: promise and limitations. Am J Hum Genet 108:25–35PubMed

39.

Pividori M, Rajagopal PS, Barbeira A, Liang Y, Melia O, Bastarache L, Park Y, GTEx Consortium, Wen X, Im HK (2020) PhenomeXcan: mapping the genome to the phenome through the transcriptome. Sci Adv 6. https://doi.org/10.1126/sciadv.aba2083

40.

GTEx Consortium (2020) The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science (1979) 369:1318–30

41.

Berisa T, Pickrell JK (2016) Approximately independent linkage disequilibrium blocks in human populations. Bioinformatics 32(2):283–285. https://doi.org/10.1093/bioinformatics/btv546CrossRefPubMed

42.

Zou Y, Carbonetto P, Wang G, Stephens M (2022) Fine-mapping from summary data with the ‘Sum of Single Effects’ model. Published Online First. https://doi.org/10.1371/journal.pgen.1010299CrossRef

43.

Wang G, Sarkar A, Carbonetto P, Stephens M (2020) A simple new approach to variable selection in regression, with application to genetic fine mapping. J R Stat Soc Series B Stat Methodol 82(5):1273–1300. https://doi.org/10.1111/rssb.12388CrossRefPubMedPubMedCentral

44.

Watanabe K, Taskesen E, van Bochoven A, Posthuma D (2017) Functional mapping and annotation of genetic associations with FUMA. Nat Commun 8:1826PubMedPubMedCentral

45.

de Leeuw CA, Mooij JM, Heskes T, Posthuma D (2015) MAGMA: generalized gene-set analysis of GWAS data. PLoS Comput Biol 11:e1004219PubMedPubMedCentral

46.

Rentzsch P, Witten D, Cooper GM, Shendure J, Kircher M (2019) CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res 47. https://doi.org/10.1093/nar/gky1016

47.

Lieberman-Aiden E, van Berkum NL, Williams L, Imakaev M, Ragoczy T, Telling A, Amit I, Lajoie BR, Sabo PJ, Dorschner MO, Sandstrom R, Bernstein B, Bender MA, Groudine M, Gnirke A, Stamatoyannopoulos J, Mirny LA, Lander ES, Dekker J (1979) Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 2009(326):289–293

48.

Orvis J, Gottfried B, Kancherla J, Adkins RS, Song Y, Dror AA, Olley D, Rose K, Chrysostomou E, Kelly MC, Milon B, Matern MS, Azaiez H, Herb B, Colantuoni C, Carter RL, Ament SA, Kelley MW, White O, Bravo HC, Mahurkar A, Hertzano R (2021) gEAR: Gene Expression Analysis Resource portal for community-driven, multi-omic data exploration. Nat Methods 18:843–844PubMedPubMedCentral

49.

Watanabe K, Stringer S, Frei O, Umićević Mirkov M, de Leeuw C, Polderman TJC, van der Sluis S, Andreassen OA, Neale BM, Posthuma D (2019) A global overview of pleiotropy and genetic architecture in complex traits. Nat Genet 51:1339–1348PubMed

50.

Hromatka BS, Tung JY, Kiefer AK, Do CB, Hinds DA, Eriksson N (2015) Genetic variants associated with motion sickness point to roles for inner ear development, neurological processes and glucose homeostasis. Hum Mol Genet 24:2700–2708PubMedPubMedCentral

51.

Rujescu D, Hartmann AM, Giegling I, Konte B, Herrling M, Himmelein S, Strupp M (2018) Genome-wide association study in vestibular neuritis: involvement of the host factor for HSV-1 replication. Front Neurol 9:1–9

52.

Strupp M, Maul S, Konte B, Hartmann AM, Giegling I, Wollenteit S, Feil K, Rujescu D (2020) A variation in FGF14 is associated with downbeat nystagmus in a genome-wide association study. Cerebellum 19:348–357PubMed

53.

Vietri Rudan M, Barrington C, Henderson S, Ernst C, Odom DT, Tanay A, Hadjur S (2015) Comparative Hi-C reveals that CTCF underlies evolution of chromosomal domain architecture. Cell Rep 10:1297–1309PubMedPubMedCentral

54.

Vidović T, Ewald CY (2022) Longevity-promoting pathways and transcription factors respond to and control extracellular matrix dynamics during aging and disease. Front Aging 3. https://doi.org/10.3389/fragi.2022.935220

55.

Rudnicki A, Isakov O, Ushakov K, Shivatzki S, Weiss I, Friedman LM, Shomron N, Avraham KB (2014) Next-generation sequencing of small RNAs from inner ear sensory epithelium identifies microRNAs and defines regulatory pathways. BMC Genomics 15:1–12

56.

Shen J, Scheffer DI, Kwan KY, Corey DP (2015) SHIELD: an integrative gene expression database for inner ear research. Database 2015:1–9

57.

Cai N, Revez JA, Adams MJ et al (2020) Minimal phenotyping yields genome-wide association signals of low specificity for major depression. Nat Genet 52(4):437–447. https://doi.org/10.1038/s41588-020-0594-5CrossRefPubMedPubMedCentral

58.

Agrawal Y, Carey JP, della Santina CC, Schubert MC, Minor LB. (2009) Disorders of balance and vestibular function in US adults: data from the National Health and Nutrition Examination Survey, 2001–2004. Arch Intern Med 169:938–944PubMed

59.

Agrawal Y, van de Berg R, Wuyts F, Walther L, Magnusson M, Oh E, Sharpe M, Strupp M (2019) Presbyvestibulopathy: diagnostic criteria consensus document of the classification committee of the Bárány Society. J Vestib Res 29:161–170PubMedPubMedCentral

60.

Kalmanson O, Foster CA (2023) Cupulolithiasis: a critical reappraisal. OTO Open 7. https://doi.org/10.1002/oto2.38

61.

Sessoms PH, Gottshall KR, Sturdy J, Viirre E (2015) Head stabilization measurements as a potential evaluation tool for comparison of persons with TBI and vestibular dysfunction with healthy controls. Mil Med 180:135–142PubMed

62.

Fu W, Zhao J, Hu W, Dai L, Jiang Z, Zhong S, Deng B, Huang Y, Wu W, Yin J (2021) LINC01224/ZNF91 promote stem cell-like properties and drive radioresistance in non-small cell lung cancer. Cancer Manag Res 13:5671–5681PubMedPubMedCentral

63.

Edwards SL, Beesley J, French JD, Dunning AM (2013) Beyond GWASs: illuminating the dark road from association to function. Am J Hum Genet 93(5):779–97. https://doi.org/10.1016/j.ajhg.2013.10.012. PMID: 24210251; PMCID: PMC3824120

64.

He D, Wu D, Muller S, Wang L, Saha P, Ahanger SH, Liu SJ, Cui M, Hong SJ, Jain M, Olson HE, Akeson M, Costello JF, Diaz A, Lim DA (2021) miRNA-independent function of long noncoding pri-miRNA loci. Proc Natl Acad Sci 118. https://doi.org/10.1073/pnas.2017562118

65.

Hunt SE, McLaren W, Gil L, Thormann A, Schuilenburg H, Sheppard D, Parton A, Armean IM, Trevanion SJ, Flicek P, Cunningham F (2018) Ensembl variation resources. Database (Oxford) 2018:bay119. https://doi.org/10.1093/database/bay119

66.

Walsh KM, Zhang C, Calvocoressi L, Hansen HM, Berchuck A, Schildkraut JM, Bondy ML, Wrensch M, Wiemels JL, Claus EB (2022) Pleiotropic MLLT10 variation confers risk of meningioma and estrogen-mediated cancers. Neurooncol Adv 4. https://doi.org/10.1093/noajnl/vdac044

67.

Stankiewicz P, Khan TN, Szafranski P, Slattery L, Streff H, Vetrini F, Bernstein JA, Brown CW, Rosenfeld JA, Rednam S, Scollon S, Bergstrom KL, Parsons DW, Plon SE, Vieira MW, Quaio CRDC, Baratela WAR, Acosta Guio JC, Armstrong R, Mehta SG, Rump P, Pfundt R, Lewandowski R, Fernandes EM, Shinde DN, Tang S, Hoyer J, Zweier C, Reis A, Bacino CA, Xiao R, Breman AM, Smith JL, Katsanis N, Bostwick B, Popp B, Davis EE, Yang Y (2017) Haploinsufficiency of the chromatin remodeler BPTF causes syndromic developmental and speech delay, postnatal microcephaly, and dysmorphic features. Am J Hum Genet 101:503–515PubMed

68.

Schmoker AM, Weinert JL, Markwood JM, Albretsen KS, Lunde ML, Weir ME, Ebert AM, Hinkle KL, Ballif BA (2020) FYN and ABL regulate the interaction networks of the DCBLD receptor family. Mol Cell Proteomics 19:1586–1601PubMedPubMedCentral

Titel: Genome-Wide Association Study of Chronic Dizziness in the Elderly Identifies Loci Implicating MLLT10, BPTF, LINC01224, and ROS1
verfasst von: Royce Clifford
Daniel Munro
Daniel Dochtermann
Poornima Devineni
Saiju Pyarajan
Francesca Telese
Abraham A. Palmer
Pejman Mohammadi
Rick Friedman
Million Veteran Program
Publikationsdatum: 30.11.2023
Verlag: Springer US
Erschienen in: Journal of the Association for Research in Otolaryngology / Ausgabe 6/2023
Print ISSN: 1525-3961
Elektronische ISSN: 1438-7573
DOI: https://doi.org/10.1007/s10162-023-00917-y

Neu im Fachgebiet HNO

Erhebliches Risiko für Kehlkopfkrebs bei mäßiger Dysplasie

29.05.2024 Larynxkarzinom Nachrichten

Fast ein Viertel der Personen mit mäßig dysplastischen Stimmlippenläsionen entwickelt einen Kehlkopftumor. Solche Personen benötigen daher eine besonders enge ärztliche Überwachung.

Hörschwäche erhöht Demenzrisiko unabhängig von Beta-Amyloid

29.05.2024 Hörstörungen Nachrichten

Hört jemand im Alter schlecht, nimmt das Hirn- und Hippocampusvolumen besonders schnell ab, was auch mit einem beschleunigten kognitiven Abbau einhergeht. Und diese Prozesse scheinen sich unabhängig von der Amyloidablagerung zu ereignen.

„Übersichtlicher Wegweiser“: Lauterbachs umstrittener Klinik-Atlas ist online

17.05.2024 Klinik aktuell Nachrichten

Sie sei „ethisch geboten“, meint Gesundheitsminister Karl Lauterbach: mehr Transparenz über die Qualität von Klinikbehandlungen. Um sie abzubilden, lässt er gegen den Widerstand vieler Länder einen virtuellen Klinik-Atlas freischalten.

Betalaktam-Allergie: praxisnahes Vorgehen beim Delabeling

16.05.2024 Pädiatrische Allergologie Nachrichten

Die große Mehrheit der vermeintlichen Penicillinallergien sind keine. Da das „Etikett“ Betalaktam-Allergie oft schon in der Kindheit erworben wird, kann ein frühzeitiges Delabeling lebenslange Vorteile bringen. Ein Team von Pädiaterinnen und Pädiatern aus Kanada stellt vor, wie sie dabei vorgehen.

Update HNO

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert – ganz bequem per eMail.

Newsletter bestellen

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Genome-Wide Association Study of Chronic Dizziness in the Elderly Identifies Loci Implicating MLLT10, BPTF, LINC01224, and ROS1