UJussi Jokinen, Adrian E. Boström, Andreas Chatzittofis, Diana M. uCiuculete, Katarina Görts Öberg, UJohn N. Flanagan, Stefan Arver, Helgi B. Schiöth
I-DOI: http://dx.doi.org/10.1016/j.psyneuen.2017.03.007
Amaphuzu avelele
- • Iziguli ezine-hypersexual disorder zazinciphise amazinga e-methylation endaweni yohlobo lwe-CRH.
- • Iziguli ezine-hypersexual disorder zazinezinga eliphakeme (TNF) -I-iqhathaniswa namavolontiya anempilo.
abstract
I-Hypersexual Disorder (HD) echazwa njengengafuneki yesifiso sobulili ngaphandle kokuphazanyiswa okuhambisana nezinto zokuphoqelela, ukufakwa kokuxakwa kanye nokuziphatha, futhi okuhlongozwayo njengokuxilongwa ku-DSM 5, yabelana ngezici ezithile ezigqagqene nenkinga yokusebenzisa izidakamizwa kufaka phakathi izinhlelo ezijwayelekile ze-neurotransmitter kanye ne-dysregulated hypothalamic-pituitary Umsebenzi we-axisal (HPA) axis. Kulolu cwaningo, oluqukethe iziguli zesilisa ze-67 HD kanye namavolontiya anempilo abesilisa abangama-39, sihlose ukukhomba amasayithi we-HPA-axis ahlanganiswe nezindawo ze-CpG, lapho ukuguqulwa kwephrofayili ye-epigenetic kuhlotshaniswa ne-hypersexuality.
Iphethini ye-genome-wide methylation ilinganiswa egazini lonke kusetshenziswa i-Illumina Infinium Methylation EPIC BeadChip, ilinganisa isimo se-methylation yezindawo ezingaphezu kwe-850 K CpG. Ngaphambi kokuhlaziywa, iphethini ye-methylation yomhlaba wonke yacutshungulwa ngokwezinqubomgomo ezijwayelekile futhi zalungiswa ngohlobo olusha lweseli lwegazi i-heterogeneity. Sifake amasayithi we-CpG akhiwe ngaphakathi kwe-2000 bp yesayithi lokuqalwa kokubhalwa kwalezinhlobo ezilandelayo ezihlanganisiwe ze-HPA-axis: I-Corticotropin ikhulula i-hormone (CRH), i-corticotropin ekhulula amaprotheni ahlanganisa i-hormone (CRHBP), i-corticotropin ekhulula i-hormone receptor 1 (CRHR1) i-receptor 2 (CRHR2), FKBP5 kanye ne-glucocorticoid receptor (NR3C1). Senze amamodeli we-regical regression regical of methylation M-values to a categorical of hypersexuality, fixation for nokudangala, dexamethasone isimo esingacindezeli, inani eliphelele lemibuzo yemibuzo ye-Childhood Traumaire namazinga we-plasma we-TNF-alpha ne-IL-6.
Ezingxenyeni ezingama-76 ezivivinyiwe ze-CpG, ezine zazibaluleke ngegama (p <0.05), ezihambisana nezakhi zofuzo i-CRH, CRHR2 ne-NR3C1. Cg23409074 – itholakala ngama-48 bp umfula we indawo yokuqala ukubhala yohlobo lwe-CRH - yaphawuleka kakhulu kwiziguli ezinesizungu ngemuva kokulungiswa kokuhlolwa okuningi kusetshenziswa indlela ye-FDR. Amazinga we-Methylation we-cg23409074 ahlanganiswe kahle nencazelo yohlobo lohlobo lwe-CRH endaweni yokuzimela yezifundo zabesilisa ezinempilo ze-11. Amazinga e-methylation endaweni esetshenzisiwe ye-CRH, i-cg23409074, ahlanganiswa kakhulu phakathi kwegazi nezifunda ezine zobuchopho ezahlukahlukene.
I-CRH ingumhlanganisi obalulekile wezimpendulo zokuxineka ze-neuroendocrine ebuchosheni, neqhaza elibalulekile ezinhlelweni zokulutha. Imiphumela yethu ikhombisa ushintsho lwe-epigenetic kuhlobo lwe-CRH oluhlobene nokukhubazeka kwe-hypersexual emadodeni.
Ingxoxo
Kulolu cwaningo, sithole ukuthi iziguli zesilisa ezine-hypersexual disorder zinciphise amazinga e-methylation endaweni ye-methylation locus (cg23409074) etholakala kwi-48 bp phezulu kwesizinda sokubhalwa kohlobo lwe-CRH. Ngaphezu kwalokho, le ndawo etholakala nge-methylation yahlobana kahle ne-CRH gene gene endaweni ezimele yezifundo zabesilisa ezinempilo. Ngokwazi kwethu, lo ngumbiko wokuqala ngoshintsho lwe-epigenetic oluphathelene ne-hypersexual disorder. Sisebenzise ama-genome wide wide methylation chips anezindawo ezingaphezu kwe-850K CpG, kodwa-ke, ngokuya ngokutholwe kwethu kwangaphambi kokudalwa kwe-HPA emadodeni ane-hypersexual disorder (I-Chatzittofis et al., 2016), sisebenzise indlela ehlosiwe ezinhlotsheni zozimele ze-eksisi ye-HPA.
I-CRH ingumhlanganisi obalulekile wezimpendulo zokuxineka kwe-neuroendocrine ebuchosheni, isimilo sokuziphatha kanye nesistimu yezinzwa ezizimele (I-Arborelius et al., 1999), kanye ne-neuroplasticity (Regev & Baram, 2014). Uma kubhekwa ukuphazamiseka kwe-hypersexual ohlakeni lwe-neurobiology yokulutha, kutholakale kahle ukuthi i-CRH inendima ebalulekile kunqubo yokulutha (I-Zorrilla et al., 2014). Kumamodeli wamagundane, uhlelo lweCRF lushayela umlutha ngezenzo ezise-amygdala enwetshiwe, ezikhiqiza isimilo esifana nokukhathazeka, ukusilela komvuzo, ukuzilawula kwezidakamizwa okuphoqelela nokuziphatha okubangelwa ukucindezela okubangelwa ukucindezela (I-Zorrilla et al., 2014). Ngaphezu kwalokho, ukwenziwa kusebenze kwama-CRF neurons ku-medial prefrontal cortex kungaba nomthelela ekulahlekelweni kokulawulwa okubonwa ezifundweni ze-HD. Kukhonjisiwe ukuthi ukusetshenziswa kwezidakamizwa okungamahlalakhona kuholela kwi-axis ye-HPA-axis enamazinga akhuphukile e-ACTH ngenkathi i-CRH idlala indima enkulu ekulamuleni izimpendulo ezingezinhle zokucindezeleka ngesikhathi sokuhoxiswa kwezidakamizwa (UKakko et al., 2008; Koob et al., 2014). Ngokufanayo, i-axis ye-HPA-axis enezinga eliphakeme le-ACTH kanye nezinguquko ze-epigenetic kuhlobo lweCRH ezigulini zesilisa ezinesifo se-hypersexual kungaholela kumbuthano wokulangazelela nokuphinda ubuye, ngesimo esisha esingesihle somzwelo, ukugcina ukuziphatha kwe-hypersexual ngomzamo oyize buyisela isimo sedysphoric ngokomzwelo. Ukuzibandakanya kaninginingi emibonweni yezocansi, ukunxusa noma isimilo ekuphenduleni isimo se-dysphoric state kanye / noma ekuphenduleni imicimbi yokuphila ecindezelayo kuyizimpawu ezisemqoka kunqubo yokuhlonza yokuphazamiseka kwesifo se-hypersexual (Kafka, 2010). Okutholakele kwethu kwe-hypomethylation yesakhi sofuzo se-CRH ehambisana nemibhangqwana ye-methylation locus okwayihambisana nge-gene expression in a cohort ezimele, ingeza kokutholwe kwangaphambilini kokuxineka kwe-axis ye-HPA kwiziguli zesilisa ezinesifo se-hypersexual esikhungweni samangqamuzana. Ukuziphatha kokuzibusa kwe-Heroin kuhlotshaniswe nokwehluka kuhlobo lwe-CRH lokusayina uhlobo oluthile lokulawulwa kokuguqulwa kwezakhi ze-methylation kumodeli yezilwane (McFalls et al., 2016) kanye ne-promoter methylation kubikwa ukuthi kunomthelela kuphethini yokubonisa ye-CRH (Chen et al., 2012). Noma kunjalo, ubukhulu bokuthi umehluko we-methylation ku-CRH gene locus (cg23409074) laliphansi impela (umehluko osho cishe i-1.60%), nokuhlobene ngokomzimba kwe Izinguquko ezicashile ze-methylation azicaciswanga ngokuphelele. Kukhona nokho, kunenqwaba yezincwadi ezikhulayo izinhlobo ezithile zofuzo, eziphakamisa imiphumela ehlukahlukene ebhaliwe yokuhumusha neyokuhumusha yokuqonda Izinguquko ze-methylation (1-5%), ikakhulukazi kuma-syndromes ayinkimbinkimbi e-multifactorial afana nokudangala noma i-schizophrenia (Leenen et al., 2016).
Kulolu cwaningo, sithathe ama-confounders afanele kakhulu, anjengokudangala, isimo se-DST sokungacindezeli, inani eliphelele le-CTQ kanye namazinga we-TNF-alpha, uma kucatshangelwa usoseshini ohlaziya phakathi kwezakhi zofuzo ezihlobene ne-HPA-axis kanye ne-hypersexual disorder . Kuyathakazelisa ukuthi iziguli ezinesifo se-hypersexual disorder zazinezinga eliphakeme kakhulu (i-TNF) -i-iqhathaniswa namavolontiya anempilo (iJokinen et al., 2016). Kufanele ekuxhumaneni phakathi kwe-glucocorticoids nokuvuvukala nomehluko weqembu ku-TNF-alpha kanye namazinga we-IL-6 phakathi kweziguli nezilawuli ezinempilo, sisebenzise izimpawu zokuvuvukala njenge-covariates to kubhekwe ukungqubuzana okungenzeka kwe-neuroinflammation ebanga eliphansi. Ukuwohloka komzimba kubalulekile ku-pathophysiology ngaphansi kwezinkinga eziningana zengqondo kubandakanya ukucindezelwa okukhulu, ukuphazamiseka kwengqondo ngokuguquguquka kwengqondo kanye ne-schizophrenia (Danzer et al., 2008). I-neuroinflammation ebanga eliphansi ijwayele ukubonwa ezigulini ezinesifo se-HPA axis dysregulation (Horowitz et al., 2013) kanti isichasiselo sokuvuvukala sigcizelela indima yezimpawu zokungasebenzi kahle kwe-psycho-neuroimmunological dysfunctions (Zunszain et al., 2013). Kungenzeka ukuthi ukuvuvukala kanye nokusayina kwe-glucocorticoid kungenzeka kusebenze ngokuzimele kuzakhiwo ezifanayo nezinqubo ngaphandle kokuhlangana okuqondile kubangele umphumela wokulimala okungeziwe; kulesi siguli iziguli zesilisa ezine-HD zazinamazinga aphezulu e-TNFISI uma kuqhathaniswa namavolontiya angabesilisa anempilo kungakhathalekile ukuthi une-HPA-axis dysregulation (Jokinen et al., 2016). As okubikwe ngaphambilini (i-Chatzittofis et al., 2016), umuthi wokulwa nokucindezela noma ubunzima bokudangala abuzange kuhlotshaniswa kakhulu nezinyathelo zomsebenzi we-HPA kulolu cwaningo lwabantu.
Ngokuqhubekayo kulolu cwaningo, ngenxa yokuthi iziguli zabika ubunzima obuningi bokuphila kwasekuqaleni uma kuqhathaniswa nezilawuli ezinempilo kanye nemiphumela eyaziwayo yokuhlukumezeka kwengane ku-epigenome, sisebenzise ubunzima besikhathi sokuqala kwempilo kumamodeli wokubuyela emuva ukubheka umphumela ongaba khona odidayo wobuntwana ukuhlukumezeka emaphethini we-methylation. I-HPA-axis dysregulation ehlobene nobunzima bempilo isencane ikhombisa ukuba sengozini kanye nomzamo wokunxeshezelwa ngemiphumela yezinkinga zobuntwana (Heim et al. 2008) nobunzima bempilo yokuqala buhlobene nezinguquko ze-epigenetic zezakhi zofuzo ezihlobene ne-HPA (I-Turecki neMeaney, i-2016).
Ukuqanjwa komqondo ngokweqile kwe-hypersexual disorder kuye kwaxoxwa kakhulu ngakho futhi yize ukuxilongwa kungafakwanga ku-DSM-5, umkhakha wokufunda ukhombisile ukwethenjwa okuphezulu nokuba semthethweni kwenqubo ehlongozwayo yokuxilongwa kwe-hypersexual disorder (Reid et al. , 2012).
Amandla ocwaningo ayisibalo seziguli ezilandelanayo ezinokuqonda okuphelele kwe-hypersexual disorder, iqembu elilawula ubudala beminyaka yamavolontiya anempilo, ngaphandle kokuphazamiseka kwengqondo okukhona manje noma kwangaphambilini futhi ngaphandle komlando womndeni wokuphazamiseka kwengqondo okukhulu kanye nokuhlukumezeka okubi kakhulu. Ngaphezu kwalokho, ukucatshangelwa kwe-confounders okungenzeka njengokuhlupheka kwengane, ukudangala, umaki we-neuroinfigueatory kanye nemiphumela yokuhlolwa kwe-dexamethasone kungabonakala njengamandla.
Ukulinganiselwa okuthile: ukuzibika kwakho kobunzima bempilo yangaphambi kokuqala kanye nokwakheka kwengxenye yocwaningo, lokho akuvumeli iziphetho ngokubandlululwa okuthile. Ngaphezu kwalokho, ngoba lolu wucwaningo lokuqala oluphenya nge-epigenomics emadodeni ane-hypersexual disorder, kungakuhle ukuphinda lokho esikutholile eqenjini elizimele lezihloko ze-HD. Ngaphezu kwalokho, ngenkathi i-cg23409074 iboniswa ukuthi ihambelana nkulumo yehlobo lohlobo lwe-CRH ezilawulweni ezinempilo, okwamanje ayikhonjiswa ukuthi lokhu kungakhombisa ukuguqulwa okungakanani kwezifundo ze-HD kanye isilinganiso se-CRF besizoba usizo kulolu cwaningo. Kudingeka ezinye izifundo ukuze kuphenywe iphathini yokuveza eyingqayizivele ye-CRH emadodeni ane-HD. An Umbuzo obalulekile uma ngabe yonke ingxenye yegazi ye-CRH methylation ikhombisa imiphumela ebuchosheni. Kusetshenziswa ithuluzi elithembekile ukuqhathanisa i-methylation phakathi kwegazi lonke nobuchopho, amazinga e-methylation at isayithi le-CRH elihlonziwe, i-cg23409074, laxhunyaniswa kakhulu phakathi kwegazi nokune okuhlukile izifunda zobuchopho, ngokuhlangana okunamandla kwe-cortex yangaphambili, isilawuli esiyisihluthulelo sokuphendula kwengcindezi. Lokhu kunikeza ukwesekelwa okuthile okungafani nesimo se-methylation esibonwa egazini lonke bonisa ukuguqulwa okwenzeka ezifundeni ezithile zobuchopho. Ngaphezu kwalokho, ukuhlaziya kwenhlangano kwe-methylation kanye nenkulumo kwenziwa eqenjini elincane lamavolontiya anempilo futhi abalulekile kumamodeli anamandla, kepha hhayi ngokuhlangana kwePearson. Lo mphumela ongqubuzanayo ungachazwa ngokuthi amamodeli alayini abaqinile anconyelwa ukuthi asetshenziswe uma kunosayizi omncane wesampula, ukuphendula nganoma yikuphi okukhishwa noma i-heteroscedasticity kudatha engaba nemiphumela emibi (Joubert et al., 2012). Ngaphezu kwalokho, ngokwenza ukucubungula kuhlaziya i-intra-ngamanye, sinciphisa kakhulu amathuba okuxaka ngenxa yokuhlukahluka okuhlanganyelanayo, Ezinye izinto ezingaphendulwanga ezingaba nomthelela zingadala ushintsho kumaphethini we-methylation, isb. Amaphethini wokudla noma amazwe ase-prandial (Rask-Andersen et al., I-2016) futhi cha okulawula ukugxila kwe-plxma ye-dexamethasone ngesikhathi se-DST (Menke et al., 2016).
Ekuphetheni ukuthola kwethu i-epigenetic isimo ku-CRH gene, oxhumanisa nezincwadi ezikumlutha we-neurobiology, emadodeni ane-hypersexual disorder, angafaka isandla ekucaciseni inqubo yamakhemikhali we-pathophysiological biology of hypersexual disorder.
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