Leveraging Enhanced Hi‐C Capture Analysis (eHiCA) to identify susceptibility genes in ambiguous GWAS loci for Alzheimer's disease: evidence for known and unusual suspects

利用增强型Hi-C捕获分析（eHiCA）识别阿尔茨海默病模糊GWAS位点中的易感基因：已知和不常见嫌疑基因的证据

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作者：Moallemian,Soodeh,Saghafi,Abolfazl,Deshpande,Rutvik,Perez,Jose M,Budak,Miray,Fausto,Bernadette A,Elahi,Fanny,Gluck,Mark A,Joseph‐Mathurin,Nelly,Gong,Katherine,Chen,Gengsheng,Massoumzadeh,Parinaz,Strain,Jeremy F,Ibanez,Laura,Gordon,Brian A,Llibre‐Guerra,Jorge J,Hassenstab,Jason J,Perrin,Richard J,Xiong,Chengjie,Bateman,Randall J,McDade,Eric,Benzinger,Tammie LS,Cruchaga,Carlos,Ponomareva,Natalya V,Andreeva,Tatiana V,Kuznetsova,Irina L,Protasova,Maria,Malina,Daria,Kunizheva,Svetlana,Kupryanova,Daria,Petrova,Victoria,Kolesnikova,Ekaterina P,Mitrofanov,Andrey,Fokin,Vitaly,Illarioshkin,Sergey N,Rogaev,Evgeny I,Kucharska‐Newton,Anna M,Chen,Jennifer,Pike,James Russell,Pleasants,Hannah,Lutsey,Pamela L,Bey,Ganga,Abner,Erin L,Whitsel,Eric A,Stewart,James D,Palta,Priya,Oomens,Julie E,Wilson,Rachael E,Reyes,Ramiro Eduardo Rea,Jonaitis,Erin M,Chin,Nathaniel A,Zetterberg,Henrik,Johnson,Sterling C,Palpatzis,Eleni,Shekari,Mahnaz,Akinci,Muge,Gispert,Juan Domingo,Fauria,Karine,Brugulat‐Serrat,Anna,Sánchez‐Benavides,Gonzalo,Arenaza‐Urquijo,Eider M,Yang,Yisu,Sathe,Aditi,Schilling,Kurt,Gaynor,Leslie S,Choi,Seo‐Eun,Klinedinst,Brandon,Lee,Michael L,Trittschuh,Emily H,Sanders,Elizabeth,Dumitrescu,Logan,Landman,Bennett A,Crane,Paul K,Hohman,Timothy J,Archer,Derek B,Boyle,Rory,Xu,Hao,Cousins,Katheryn A Q,Dehghani,Nadia,Morse,Colleen,Verma,Anurag,Shaw,Leslie M,Massimo,Lauren,Zhou,Wanding,Wolk,David A,McMillan,Corey T,Biobank,Penn Medicine,Shi,Jiong,Xu,Yun,Zhao,Shenyu,Yu,Jin‐Tai,Wang,Kai,Zhao,Jiehao,Li,Yi,Xie,Chunming,Zhang,Qing'e,Chen,Qidong,Li,Xia,Peng,Guoping,Yang,Li,Ji,Yong,Cheng,Zhaozhao,Lv,Xinyi,Wang,Qiong,Wang,Xinning,Zhuang,Junpeng,Qiu,Hongyan,Xu,Ye,Feng,Sheng,Wang,Yuqi,Cheng,Gang,Lachner,Christian,Emrani,Sheina,Kuchenbecker,Lindsey A,Dunlop,Sara R,Rawlinson,Bailey D,Engelberg‐Cook,Erica,Ventura,Josalen,Velez‐Uribe,Idaly,Peng,Zhongwei,Haydu,Lauren,Dickson,Dennis W,Graff‐Radford,Neill R,Day,Gregory S,Lucas,John A,Murray,Melissa E,Xia,Ying,Dore,Vincent,Fripp,Jurgen,Bourgeat,Pierrick,Lim,Yen,Laws,Simon M,Fowler,Christopher J,Rowe,Christopher C,Masters,Colin L,Coulson,Elizabeth J,Maruff,Paul,Anastasi,Federica,Escalante,Armand González,Segura‐Retana,Pol,Ortiz‐Romero,Paula,Sánchez‐Benavides,Gonzalo,López‐Martos,David,Grau‐Rivera,Oriol,Minguillón,Carolina,del Campo,Marta,Vilor‐Tejedor,Natalia,Suárez‐Calvet,Marc,Yin,Zheng,Teng,Ling,Zhang,Ya,Gagliardi,David W,Johnson,Ryan,Adamowicz,David H,Wang,Jijing,Liu,Lei,Chhatwal,Jasmeer P,Jager,Philip L De,Bennett,David A A,Schneider,Julie A,Petyuk,Vladislav A,Menon,Vilas,Yang,Hyun‐Sik,Ruthirakuhan,Myuri,Wong,Yuen Yan,Perfetto,Sofia,Xiong,Lisa Y,Wu,Che‐Yuan,Ryoo,Si Won,Mori‐Fegan,Daniel K,Chenoweth,Meghan J,Swardfager,Walter,Sharmin,Tahmida,Chatterjee,Pratishtha,Doecke,James D,Ashton,Nicholas,Sohrabi,Hamid R,Zetterberg,Henrik,Blennow,Kaj,Garg,Manohar,Martins,Ralph N,Joseph‐Mathurin,Nelly,Gong,Katherine,Chen,Gengsheng,Massoumzadeh,Parinaz,Strain,Jeremy F,Ibanez,Laura,Gordon,Brian A,Llibre‐Guerra,Jorge J,Hassenstab,Jason J,Perrin,Richard J,Xiong,Chengjie,Bateman,Randall J,McDade,Eric,Benzinger,Tammie LS,Cruchaga,Carlos,Whitmer,Rachel A,Snyder,Heather M,Hill,Marcus,Robinson,Chartay,Alexander,Ashley,Tang,Tara,Meyer,Oanh L,Omotoye,Elizabeth,Williams,Kelvin,Lovato,Laura,Woolard,Nancy,Kivipelto,Miia,Espeland,Mark A,Baker,Laura D,Carrillo,Maria C,Hammers,Dustin B,Eloyan,Ani,Thangarajah,Maryanne,Taurone,Alexander,Kirby,Kala,Dage,Jeffrey L,Nudelman,Kelly N,Carrillo,Maria C,Rabinovici,Gil D,Dickerson,Brad C,Apostolova,Liana G,Thal,Dietmar Rudolf,Li,Xiaohang,Konstatoulea,Katerina,Gawor,Klara,Wiedmer,Anne,von Arnim,Christine AF,Vandenberghe,Rik,Carpentier,Sebastien,Otto,Markus,Schymkowitz,Joost,Rousseau,Frederic,Schaeverbeke,Jolien,Palpatzis,Eleni,Aguilar,Pablo,Colceriu,Carmen M,López,Alex,Zsadanyi,Sara E,Franquesa‐Mullerat,María,Petricola,Sami,Valentín,Antonia,Lleó,Alberto,Fortea,Juan,Bejanin,Alexandre,Arenaza‐Urquijo,Eider M,Anastassiadis,Chloe,Thapa,Simrika,Vasilevskaya,Anna,Cortez,Kasey,Dimal,Nico Paulo,Tsang,Michelle,Couto,Blas,Tang‐Wai,David F,Fox,Susan,Kovacs,Gabor G,Lang,Anthony E,Kivisäkk,Pia,Hyman,Bradley T,Arnold,Steven E,Ingelsson,Martin,Tartaglia,Carmela,Behrenbruch,Niklas,Schwarck,Svenja,Schumann‐Werner,Beate,Molloy,Eóin N,Hochkeppler,Anne,Büchel,Anna‐Therese,Moyano,Jose Bernal,Incesoy,Enise I,Garcia‐Garcia,Berta,Vockert,Niklas,Morgado,Barbara,Fischer,Larissa,Müller,Patrick,Behnisch,Gusalija,Seidenbecher,Constanze I,Schott,Björn H,Esselmann,Hermann,Wiltfang,Jens,Barthel,Henryk,Sabri,Osama,Kreissl,Michael C,Düzel,Emrah,Maass,Anne,Feizpour,Azadeh,Bourgeat,Pierrick,Dore,Vincent,Doecke,James D,Canovas,Rodrigo,Laws,Simon M,Porter,Tenielle,Huang,Kun,Fowler,Christopher J,Weiner,Michael W,Morris,John C,Benzinger,Tammie LS,Schindler,Suzanne E,Bateman,Randall J,Ward,Larry,Fripp,Jurgen,Masters,Colin L,Villemagne,Victor L,Rowe,Christopher C,Tan,Jazlynn Xiu Min,Kang,Min Su,Yeh,Yi‐Hsuan,Rahmouni,Nesrine,Bezgin,Gleb,Lussier,Firoza Z,Hong,Seok Jun,Isen,Jonah,McLaurin,JoAnne,Bernhardt,Boris,Stefanovic,Bojana,Soucy,Jean‐Paul,Gauthier,Serge,Black,Sandra E,Rosa‐Neto,Pedro,Goubran,Maged,Ottoy,Julie,Gulhan,Ali,Tejeda,Marlene,Newman,Caitlin,Farrell,John J,Zhu,Congcong,Wetzler,Lee,Lunetta,Kathryn L,Bush,William S,Martin,Eden R,Wang,Li‐San,Schellenberg,Gerald D,Pericak‐Vance,Margaret,Haines,Jonathan L,Farrer,Lindsay A,Sherva,Richard,Fernández‐Bonet,Alba,Genius,Patricia,Rodríguez‐Fernández,Blanca,Escalante,Armand González,Huguet,Jordi,Esteller,Manel,Cirach,Marta,Nieuwenhuijsen,Mark,Buongiorno,Mariateresa,Sánchez‐Benavides,Gonzalo,Grau‐Rivera,Oriol,Vállez‐Garcia,David,Navarro,Arcadi,Evans,Tavia E,Vilor‐Tejedor,Natalia,Cacciaglia,Raffaele,Escalante,Armand González,Ortiz‐Romero,Paula,Grau‐Rivera,Oriol,Sánchez‐Benavides,Gonzalo,Day,Theresa A,Blennow,Kaj,Zetterberg,Henrik,Molinuevo,Jose Luis,Gispert,Juan Domingo,Suárez‐Calvet,Marc,Salvadó,Gemma,Arunachalam,Prithvi,Treves,Francesca,Pieperhoff,Leonard,Lorenzini,Luigi,Tranfa,Mario,Masserini,Federico,Preti,Maria G,Pontillo,Giuseppe,Collij,Lyduine E,Broeders,Tommy A A,Schoonheim,Menno M,Douw,Linda,Ritchie,Craig,Boada,Mercè,Marquié,Marta,Visser,Pieter Jelle,Gispert,Juan Domingo,Cole,James H,Barkhof,Frederik,Wink,Alle Meije,Kassinopoulos,Michalis,Lizarraga,Aldana,Shekari,Mahnaz,Huguet,Jordi,Suárez‐Calvet,Marc,Milá‐Alomá,Marta,Blennow,Kaj,Zetterberg,Henrik,Kollmorgen,Gwendlyn,Quijano‐Rubio,Clara,Gispert,Juan Domingo,Salvadó,Gemma,Vállez‐Garcia,David,Cacciaglia,Raffaele,Gallay,Clara,Huguet,Jordi,Escalante,Armand González,Zetterberg,Henrik,Blennow,Kaj,Fernández‐Arcos,Ana,Suárez‐Calvet,Marc,Sundermann,Erin E,Gispert,Juan Domingo,Grau‐Rivera,Oriol,Brugulat‐Serrat,Anna,Brugulat‐Serrat,Anna,Gallay,Clara,Sánchez‐Benavides,Gonzalo,López‐Martos,David,Fernández‐Arcos,Ana,Zetterberg,Henrik,Blennow,Kaj,Suárez‐Calvet,Marc,Grau‐Rivera,Oriol,Gispert,Juan Domingo,Sundermann,Erin E,de Bittencourt,Marcelo Madrid,Baldasso,Gabriela Mantovani,Bastiani,Marco Antônio De,Limberger,Christian,da Rocha,João Batista Teixeira,Souza,Diogo O,Zimmer,Eduardo R,Smith,Patrick J,Johnson,Kim G,Roth,Heidi L,Potter,Guy G,Patillo,Sara,Lin,Weili J,Song,Allen J,Berger,Miles,O'Brien,Richard J,Liu,Andy,Lutz,Michael W,Luo,Sheng,Bozoki,Andrea,Welsh‐Bohmer,Kathleen A,Garden,Gwenn A,Whitson,Heather,Farris,Chad William,Durape,Shruti,Burton,Rebecca,Chien‐Young,Kurtis,Price,Eden,Joshi,Prajakta S,Liu,Yulin,Ang,Ting Fang Alvin,Gurnani,Ashita S,Katz,Douglas I,Tripodis,Yorghos,Alosco,Michael L,Dams‐O'Connor,Kristen,Au,Rhoda,Mez,Jesse,Farris,Chad William,Durape,Shruti,Burton,Rebecca,Chien‐Young,Kurtis,Price,Eden,Joshi,Prajakta S,Liu,Yulin,Ang,Ting Fang Alvin,Gurnani,Ashita S,Katz,Douglas I,Tripodis,Yorghos,Alosco,Michael L,Dams‐O'Connor,Kristen,Au,Rhoda,Mez,Jesse,Tan,Jazlynn Xiu Min,Kang,Min Su,Yeh,Yi‐Hsuan,Rahmouni,Nesrine,Bezgin,Gleb,Lussier,Firoza Z,Hong,Seok Jun,Isen,Jonah,McLaurin,JoAnne,Bernhardt,Boris,Stefanovic,Bojana,Soucy,Jean‐Paul,Gauthier,Serge,Black,Sandra E,Rosa‐Neto,Pedro,Goubran,Maged,Ottoy,Julie,George,Grace C,Keller,Sarah A,Powell,W Ryan,Buckingham,William R,Bendlin,Barbara B,Abner,Erin L,Apostolova,Liana G,Carrion,Carmen,Karikari,Thomas K,Meyer,Oanh L,Rissman,Robert A,Espinoza,Patricia Rodriguez,Whitmer,Rachel A,Kind,Amy JH,Janve,Vaibhav A,Seto,Mabel,Klinger,Hannah M,Brown,Jane A,Sperling,Reisa A,Aisen,Paul S,Rissman,Robert A,Koran,Mary Ellen I,Dumitrescu,Logan,Buckley,Rachel F,Hohman,Timothy J,Feizpour,Azadeh,Bourgeat,Pierrick,Dore,Vincent,Doecke,James D,Canovas,Rodrigo,Laws,Simon M,Porter,Tenielle,Huang,Kun,Fowler,Christopher J,Weiner,Michael W,Morris,John C,Benzinger,Tammie LS,Schindler,Suzanne E,Bateman,Randall J,Ward,Larry,Fripp,Jurgen,Masters,Colin L,Villemagne,Victor L,Rowe,Christopher C,Behrenbruch,Niklas,Schwarck,Svenja,Schumann‐Werner,Beate,Molloy,Eóin N,Hochkeppler,Anne,Büchel,Anna‐Therese,Moyano,Jose Bernal,Incesoy,Enise I,Garcia‐Garcia,Berta,Vockert,Niklas,Morgado,Barbara,Fischer,Larissa,Müller,Patrick,Behnisch,Gusalija,Seidenbecher,Constanze I,Schott,Björn H,Esselmann,Hermann,Wiltfang,Jens,Barthel,Henryk,Sabri,Osama,Kreissl,Michael C,Düzel,Emrah,Maass,Anne,Santos‐Santos,Miguel A,Grasso,Stephanie M,Calabria,Marco,Sala,Isabel,Sánchez‐Saudinós,María Belén,Vaqué‐Alcázar,Lídia,Bejanin,Alexandre,Carmona‐Iragui,Maria,Barroeta,Isabel,Illán‐Gala,Ignacio,Fortea,Juan,Belbin,Olivia,Alcolea,Daniel,Lleó,Alberto,de Bittencourt,Marcelo Madrid,Baldasso,Gabriela Mantovani,De Bastiani,Marco Antônio,Limberger,Christian,da Rocha,João Batista Teixeira,Souza,Diogo O,Zimmer,Eduardo R,Arunachalam,Prithvi,Treves,Francesca,Pieperhoff,Leonard,Lorenzini,Luigi,Tranfa,Mario,Masserini,Federico,Preti,Maria G,Pontillo,Giuseppe,Collij,Lyduine E,Broeders,Tommy A A,Schoonheim,Menno M,Douw,Linda,Ritchie,Craig,Boada,Mercè,Marquié,Marta,Visser,Pieter Jelle,Gispert,Juan Domingo,Cole,James H,Barkhof,Frederik,Wink,Alle Meije,de Bittencourt,Marcelo Madrid,Baldasso,Gabriela Mantovani,Limberger,Christian,Hoffmeister,Gabriel Lermen,de Souza,Débora Guerini,da Rocha,João Batista Teixeira,Zimmer,Eduardo R,Qiao,Min N,Bhattarai,Prabesh,Yilmaz,Elanur,Rookyard,Alexander W,Das,Lipi N,Zerlin‐Esteves,Marielba,Reyes‐Dumeyer,Dolly,Lee,Annie J,Lantigua,Rafael A,Medrano,Martin,Mejia,Diones Rivera,Honig,Lawrence S,Brown,Lewis M,Kizil,Caghan,Mayeux,Richard,Vardarajan,Badri N,Sannemann,Lena,Buerger,Katharina,Hellmann‐Regen,Julian,Kleineidam,Luca,Laske,Christoph,Perneczky,Robert,Peters,Oliver,Priller,Josef,Ramirez,Alfredo,Schneider,Anja,Spottke,Annika,Synofzik,Matthis,Teipel,Stefan J,Wagner,Michael,Wiltfang,Jens,Yakupov,Renat,Düzel,Emrah,Jessen,Frank,Lizarraga,Aldana,Kassinopoulos,Michalis,González‐de‐Echávarri,José María,Huguet,Jordi,Sánchez‐Benavides,Gonzalo,Grau‐Rivera,Oriol,Suarez‐Calvet,Marc,Milà‐Alomà,Marta,Blennow,Kaj,Zetterberg,Henrik,Kollmorgen,Gwendlyn,Quijano‐Rubio,Clara,Gispert,Juan Domingo,Salvadó,Gemma,Cacciaglia,Raffaele,Nuytemans,Karen,Wang,Liyong,Nasciben,Luciana Bertholim,Xu,Wanying,Liu,Xiaoxiao,Rajabli,Farid,Celis,Katrina,Lu,Leina,Gearing,Marla,Bennett,David A A,Flanagan,Margaret E,Weintraub,Sandra,Geula,Changiz,Schuck,Theresa,Scott,William K,Dykxhoorn,Derek M,Griswold,Anthony J,Pericak‐Vance,Margaret,Young,Juan I,Jin,Fulai,Vance,Jeffery M
期刊：影响因子：
时间：2025起止号：2025 Dec;21(Suppl 1)
doi：10.1101/2025.05.22.655574

Abstract

BACKGROUND: The identification of susceptibility genes in noncoding genome‐wide association study (GWAS) loci remains a challenge as interactions between regulatory elements and targets can span several Mb and exceed 1:1 ratio of element‐to‐target. For several noncoding AD GWAS loci, the variant(s) and gene target(s) likely to be driving the association have been difficult to determine, with multiple or no clear candidate genes. To identify underlying susceptibility gene(s) in these “ambiguous” loci, we queried an in‐house high‐resolution Hi‐C database of genomic interactions in multiple genomic ancestries. METHOD: Hi‐C libraries were constructed using brain frontal cortex and iPSC‐derived AD relevant cells from donors matched for age, sex, and APOE genotype. We used Enhanced Hi‐C Capture analyses (eHiCA), incorporating the DeepLoop pipeline with 5kb resolution and 5kb bait windows surrounding the top GWAS and LD variants, to map chromatin loops using Hi‐C data. In our initial analyses, we applied eHiCA to uncover the regulatory architecture in six ambiguous loci from the Bellenguez et al GWAS in non‐Hispanic whites (NHW). RESULT: In the PICALM/EED locus, we found PICALM as the susceptibility gene with the strongest evidence, though lower‐level interaction with the EED promoter and regions surrounding GWAS LD variants were also observed. Interestingly, in the USP6NL/ECHDC3 and BCKDK/KAT8 loci, multiple candidate genes other than the closest genes to the LD variants were looped to the GWAS LD variants, including CELF2 and SETD1A, respectively. For two other loci (EPDR1/NME8 and MINDY2/ADAM10), the most likely candidates were the gene after which each locus was named (NME8 and ADAM10), with evidence supporting GWAS variants located in promoter or enhancer sites looping back to those genes. Interactions observed in the UNC5CL/TREM2 locus did not identify TREM2 or any other gene promoter as a likely target but showed interaction with an enhancer supporting potential indirect effects. CONCLUSION: This initial application of eHiCA on ambiguous AD GWAS loci demonstrates the utility of chromatin regulatory maps in nominating candidate genes of GWAS hits in non‐coding loci which lack clear candidates. This extended application of eHiCA will broaden our understanding of AD genomics overall.

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