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<p>Recent studies suggest that copy number variants (CNVs) may contribute to the missing heritability of complex diseases such as Alzheimer’s disease (AD) and related dementias (ADRD). We performed a CNV analysis using genotyping data (Axiom 815 K Spanish biobank array) from the GR@ACE/DEGESCO dementia dataset (<i>n</i> = 20,067) of the Spanish population. Applying PennCNV and extensive quality control, 8275 controls and 7818 dementia cases were selected for gene-level case/control associations. We identified 43,833 CNVs with deletions (47%) and duplications (53%). No genome-wide significant associations were found, but nominal associations were observed in <i>PKP3</i>-<i>SIGIRR</i> and <i>FBRSL1</i> loci. CNVs in 2970 genes were exclusive to dementia cases and enriched in vascular-related pathways. Notable findings included 14q11.2 duplication and <i>VPS13B</i> deletions in ADRD cases, the latter confirmed by optical genome mapping. Our findings suggest potential novel genes associated with ADRD in the Spanish population. However, the limited resolution of array-based technologies in detecting CNVs warrants further investigation.</p>

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Landscape of copy number variants in Spanish people with dementia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月30日

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  • Itziar de Rojas,
  • Pablo García-González,
  • Clàudia Olivé,
  • Raquel Puerta,
  • Laura Montrreal,
  • Montserrat Alegret,
  • Oscar Sotolongo-Grau,
  • Amanda Cano,
  • Marta Marquié,
  • Sergi Valero,
  • Miguel Calero,
  • Alberto Rábano,
  • Ana Belén Pastor,
  • Teodoro del Ser,
  • Inés Quintela,
  • Juan Macías,
  • Anaïs Corma-Gómez,
  • Juan A. Pineda,
  • Emilio Franco-Macías,
  • Dolores Buiza-Rueda,
  • María Bernal Sánchez-Arjona,
  • Jose Luis Royo,
  • Silvia Mendoza,
  • Carmen Lage,
  • Carmen Antúnez,
  • Arturo Corbatón-Anchuelo,
  • María Teresa Martínez-Larrad,
  • Mónica Diez-Fairen,
  • Ignacio Alvarez,
  • Raquel Huerto Vilas,
  • Alfonso Arias Pastor,
  • Manuel Menéndez-González,
  • Carmen Martínez Rodríguez,
  • Irene Rosas Allende,
  • Sebastián García-Madrona,
  • Ana Frank-García,
  • Angel Martín-Montes,
  • Miquel Baquero,
  • Nuria Aguilera,
  • Montserrat Alegret,
  • Paula Bayón-Buján,
  • Natali Bein,
  • Josep Blazquez-Folch,
  • Mercè Boada,
  • Mar Buendia,
  • Amanda Cano,
  • Berta Calm,
  • Pilar Cañabate,
  • Maria Capdevila-Bayo,
  • Angel Carracedo,
  • A. Corbatón-Anchuelo,
  • Federico Casales,
  • Itziar de Rojas,
  • Susana Diego,
  • Ana Espinosa,
  • Maria Victoria Fernandez,
  • Anna Gailhajenet,
  • Pablo García-González,
  • Marina Guitart,
  • Marta Ibarria,
  • Asunción Lafuente,
  • Núria Lleonart,
  • Juan Macias,
  • Olalla Maroñas,
  • Elvira Martín,
  • Maria Teresa Martínez,
  • Marta Marquié,
  • Andrea Miguel,
  • Laura Montrreal,
  • Xavier Morató,
  • Mariola Moreno,
  • Nathalia Muñoz,
  • Álvaro Muñoz-Morales,
  • Clàudia Olivé,
  • Gemma Ortega,
  • Ana Pancho,
  • Ester Pelejà,
  • Alba Pérez-Cordon,
  • Raquel Puerta,
  • Silvia Preckler,
  • Inés Quintela,
  • Luis Miguel Real,
  • José Nelet Rodríguez,
  • Maitee Rosende-Roca,
  • Agustín Ruiz,
  • Maria Eugenia Sáez,
  • Angela Sanabria,
  • Susanna Seguer,
  • Luís Tárraga,
  • Juan Pablo Tartari,
  • Sergi Valero,
  • Liliana Vargas,
  • Astrid Daniela Adarmes-Gómez,
  • Miquel Aguilar,
  • Daniel Alcolea,
  • Montserrat Alegret,
  • María Dolores Alonso,
  • Ignacio Alvarez,
  • Victoria Álvarez,
  • Guillermo Amer-Ferrer,
  • Martirio Antequera,
  • Anna Antonell,
  • Carmen Antúnez,
  • Alfonso Arias Pastor,
  • Miquel Baquero,
  • Olivia Belbin,
  • María Bernal Sánchez-Arjona,
  • Mercè Boada,
  • Marta Bonilla-Toribio,
  • Dolores Buiza-Rueda,
  • María Jesús Bullido,
  • Maria Teresa Buongiorno,
  • Miguel Calero,
  • Ana Camara,
  • Pilar Cañabate,
  • Fernando Cardona Serrate,
  • Ángel Carracedo,
  • Fátima Carrillo,
  • María José Casajeros,
  • Consuselo Chafer Pericás,
  • Yaroslau Compta,
  • Arturo Corbatón-Anchuelo,
  • Anaïs Corma-Gómez,
  • Paz de la Guía,
  • Itziar de Rojas,
  • Teodoro del Ser,
  • Rafael Díaz Belloso,
  • Mónica Diez-Fairen,
  • Oriol Dols-Icardo,
  • María Elena Erro Aguirre,
  • Ana Espinosa,
  • Manuel Fernandez,
  • Maria Victoria Fernández,
  • Marta Fernández-Fuertes,
  • Juan Fortea,
  • Emilio Franco-Macías,
  • Ana Frank-García,
  • Jose María García-Alberca,
  • Sergio García-Díaz,
  • Sebastián García-Madrona,
  • Guillermo Garcia-Ribas,
  • Ernesto García-Roldán,
  • Lorena Garrote-Espina,
  • Pilar Gómez-Garre,
  • Raquel Huerto Vilas,
  • Ignacio Illán-Gala,
  • Silvia Jesús,
  • Jaime Kulisevsky,
  • Miguel Angel Labrador Espinosa ,
  • Carmen Lage,
  • Agustina Legaz,
  • Alberto Lleó,
  • Sara López-García,
  • Adolfo Lopez de Munain ,
  • Juan Macías,
  • Daniel Macias-García,
  • Salvadora Manzanares,
  • Marta Marín,
  • Juan Marín-Muñoz,
  • Marta Marquié,
  • Maria Marti,
  • Miguel Martín-Bórnez,
  • Angel Martín-Montes,
  • Angel Martín Montés,
  • Victoriana Martínez,
  • Begoña Martínez,
  • Pablo Martínez-Lage Álvarez,
  • María Teresa Martínez-Larrad,
  • Marian Martinez de Pancorbo ,
  • Carmen Martínez Rodríguez,
  • Miguel Medina,
  • Maite Mendioroz Iriarte,
  • Silvia Mendoza,
  • Manuel Menéndez-González,
  • Pablo Mir,
  • Laura Molina-Porcel,
  • Fermin Moreno,
  • Esteban Muñoz,
  • Laura Muñoz-Delgado,
  • Fuensanta Noguera Perea,
  • Gemma Ortega,
  • Javier Pagonabarraga,
  • Celia Painous,
  • Ana Belén Pastor,
  • Pau Pastor,
  • Ester Pelejá,
  • Alba Pérez-Cordón,
  • Jordi Pérez-Tur,
  • María Teresa Periñán,
  • Juan Antonio Pineda,
  • Rocío Pineda-Sánchez,
  • Gerard Piñol-Ripoll,
  • Inés Quintela,
  • Alberto Rábano,
  • Luis Miguel Real,
  • Diego Real de Asúa,
  • Eloy Rodriguez-Rodriguez,
  • Irene Rosas Allende,
  • Maitée Rosende-Roca,
  • Jose Luis Royo,
  • Agustín Ruiz,
  • María Eugenia Sáez,
  • Ángela Sanabria,
  • Pascual Sánchez-Juan,
  • Raquel Sánchez-Valle,
  • Javier Sánchez-Ruiz de Gordoa ,
  • Isabel Sastre,
  • Oscar Sotolongo-Grau,
  • Lluís Tárraga,
  • Sergi Valero,
  • Francesc Valldeoriola,
  • María Pilar Vicente,
  • Laura Vivancos-Moreau,
  • Jordi Pérez-Tur,
  • María J. Bullido,
  • Guillermo Garcia-Ribas,
  • Victoria Álvarez,
  • Gerard Piñol-Ripoll,
  • Pau Pastor,
  • Eloy Rodriguez-Rodriguez,
  • Jose María García-Alberca,
  • Pablo Mir,
  • Luis M. Real,
  • Miguel Medina,
  • María Eugenia Sáez,
  • Ángel Carracedo,
  • Michael T. Heneka,
  • Lluís Tàrraga,
  • Mercè Boada,
  • Pascual Sánchez-Juan,
  • M. Victoria Fernández,
  • Sven J. van der Lee,
  • Agustín Ruiz

摘要

Recent studies suggest that copy number variants (CNVs) may contribute to the missing heritability of complex diseases such as Alzheimer’s disease (AD) and related dementias (ADRD). We performed a CNV analysis using genotyping data (Axiom 815 K Spanish biobank array) from the GR@ACE/DEGESCO dementia dataset (n = 20,067) of the Spanish population. Applying PennCNV and extensive quality control, 8275 controls and 7818 dementia cases were selected for gene-level case/control associations. We identified 43,833 CNVs with deletions (47%) and duplications (53%). No genome-wide significant associations were found, but nominal associations were observed in PKP3-SIGIRR and FBRSL1 loci. CNVs in 2970 genes were exclusive to dementia cases and enriched in vascular-related pathways. Notable findings included 14q11.2 duplication and VPS13B deletions in ADRD cases, the latter confirmed by optical genome mapping. Our findings suggest potential novel genes associated with ADRD in the Spanish population. However, the limited resolution of array-based technologies in detecting CNVs warrants further investigation.