Long runs of homozygosity are associated with Alzheimer's disease
Por:
Moreno-Grau, S, Fernandez, MV, de Rojas, I, Garcia-Gonzalez, P, Hernandez, I, Farias, F, Budde, JP, Quintela, I, Madrid, L, Gonzalez-Perez, A, Montrreal, L, Alarcon-Martin, E, Alegret, M, Maronas, O, Pineda, JA, Macias, J, Marquie, M, Valero, S, Benaque, A, Clarimon, J, Bullido, MJ, Garcia-Ribas, G, Pastor, P, Sanchez-Juan, P, Alvarez, V, Pinol-Ripoll, G, Garcia-Alberca, JM, Royo, JL, Franco-Macias, E, Mir, P, Calero, M, Medina, M, Rabano, A, Avila, J, Antunez, C, Real, LM, Orellana, A, Carracedo, A, Saez, ME, Tarraga, L, Boada, M, Cruchaga, C, Ruiz, A, Blesa, R., Fortea J., Lleó A., Vivancos, L.
Publicada:
24 feb 2021
Resumen:
Long runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer's disease (AD); however, their search has been poorly assessed to date. To investigate homozygosity in AD, here we performed a fine-scale ROH analysis using 10 independent cohorts of European ancestry (11,919 AD cases and 9181 controls.) We detected an increase of homozygosity in AD cases compared to controls [beta(AVROH) (CI 95%) = 0.070 (0.037-0.104); P = 3.91 x 10(-5); beta(FROH) (CI95%) = 0.043 (0.009-0.076); P = 0.013]. ROHs increasing the risk of AD (OR > 1) were significantly overrepresented compared to ROHs increasing protection (p < 2.20 x 10(-16)). A significant ROH association with AD risk was detected upstream the HS3ST1 locus (chr4:11,189,482-11,305,456), (beta (CI 95%) = 1.09 (0.48 - 1.48), p value = 9.03 x 10(-4)), previously related to AD. Next, to search for recessive candidate variants in ROHs, we constructed a homozygosity map of inbred AD cases extracted from an outbred population and explored ROH regions in whole-exome sequencing data (N = 1449). We detected a candidate marker, rs117458494, mapped in the SPON1 locus, which has been previously associated with amyloid metabolism. Here, we provide a research framework to look for recessive variants in AD using outbred populations. Our results showed that AD cases have enriched homozygosity, suggesting that recessive effects may explain a proportion of AD heritability.
Filiaciones:
Moreno-Grau, S:
Univ Int Catalunya, Inst Catala Neurociencies Aplicades, Res Ctr & Memory Clin, Fundacio ACE, Barcelona, Spain
Carlos III Inst Hlth, Ctr Networked Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Fernandez, MV:
Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO USA
de Rojas, I:
Univ Int Catalunya, Inst Catala Neurociencies Aplicades, Res Ctr & Memory Clin, Fundacio ACE, Barcelona, Spain
Carlos III Inst Hlth, Ctr Networked Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Garcia-Gonzalez, P:
Univ Int Catalunya, Inst Catala Neurociencies Aplicades, Res Ctr & Memory Clin, Fundacio ACE, Barcelona, Spain
Hernandez, I:
Univ Int Catalunya, Inst Catala Neurociencies Aplicades, Res Ctr & Memory Clin, Fundacio ACE, Barcelona, Spain
Farias, F:
Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO USA
Budde, JP:
Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO USA
Quintela, I:
Univ Santiago de Compostela, Grp Med Xen, Ctr Nacl Genotipado CEGEN PRB3 ISCIII, Santiago De Compostela, Spain
Madrid, L:
CAEBI Ctr Andaluz Estudios Bioinformat, Seville, Spain
Gonzalez-Perez, A:
CAEBI Ctr Andaluz Estudios Bioinformat, Seville, Spain
Montrreal, L:
Univ Int Catalunya, Inst Catala Neurociencies Aplicades, Res Ctr & Memory Clin, Fundacio ACE, Barcelona, Spain
Alarcon-Martin, E:
Univ Int Catalunya, Inst Catala Neurociencies Aplicades, Res Ctr & Memory Clin, Fundacio ACE, Barcelona, Spain
Alegret, M:
Univ Int Catalunya, Inst Catala Neurociencies Aplicades, Res Ctr & Memory Clin, Fundacio ACE, Barcelona, Spain
Maronas, O:
Univ Santiago de Compostela, Grp Med Xen, Ctr Nacl Genotipado CEGEN PRB3 ISCIII, Santiago De Compostela, Spain
Pineda, JA:
Hosp Univ Valme, Unidad Clin Enfermedades Infecciosas & Microbiol, Seville, Spain
Macias, J:
Hosp Univ Valme, Unidad Clin Enfermedades Infecciosas & Microbiol, Seville, Spain
Marquie, M:
Univ Int Catalunya, Inst Catala Neurociencies Aplicades, Res Ctr & Memory Clin, Fundacio ACE, Barcelona, Spain
Carlos III Inst Hlth, Ctr Networked Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Valero, S:
Univ Int Catalunya, Inst Catala Neurociencies Aplicades, Res Ctr & Memory Clin, Fundacio ACE, Barcelona, Spain
Carlos III Inst Hlth, Ctr Networked Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Benaque, A:
Univ Int Catalunya, Inst Catala Neurociencies Aplicades, Res Ctr & Memory Clin, Fundacio ACE, Barcelona, Spain
Clarimon, J:
Carlos III Inst Hlth, Ctr Networked Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & Sant Pau, Dept Neurol, Memory Unit, Barcelona, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & Sant Pau, Sant Pau Biomed Res Inst, Barcelona, Spain
Bullido, MJ:
Carlos III Inst Hlth, Ctr Networked Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Univ Autonoma Madrid, Ctr Biol Mol Severo Ochoa CSIC UAM, Madrid, Spain
Inst Invest Sanitaria Hosp Paz IdIPaz, Madrid, Spain
Garcia-Ribas, G:
Hosp Univ Ramon y Cajal, Madrid, Spain
Pastor, P:
Univ Barcelona, Sch Med, Hosp Univ Mutua Terrassa, Fundacio Recerca Biomed & Social Mutua Terrassa, Barcelona, Spain
Univ Barcelona, Sch Med, Hosp Univ Mutua Terrassa, Memory Disorders Unit,Dept Neurol, Barcelona, Spain
Sanchez-Juan, P:
Carlos III Inst Hlth, Ctr Networked Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Univ Cantabria, Neurol Serv, Marques Valdecilla Univ Hosp, Santander, Spain
IDIVAL, Santander, Spain
Alvarez, V:
Hosp Univ Cent Asturias, Lab Genet, Oviedo, Spain
Inst Invest Biosanitaria Principado Asturias ISPA, Oviedo, Spain
Pinol-Ripoll, G:
Carlos III Inst Hlth, Ctr Networked Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Hosp Univ Santa Maria Lleida, Inst Recerca Biomed Lleida IRBLLeida, Unitat Trastorns Cognitius, Lleida, Spain
Garcia-Alberca, JM:
Andalusian Inst Neurosci, Alzheimer Res Ctr & Memory Clin, Malaga, Spain
Royo, JL:
Univ Malaga, Sch Med, Dept Surg Biochem & Mol Biol, Malaga, Spain
Franco-Macias, E:
Univ Seville, Hosp Univ Virgen Rocio, Inst Biomed Sevilla IBiS, Unidad Demencias,Serv Neurol & Neurofisiol,CSIC, Seville, Spain
Mir, P:
Carlos III Inst Hlth, Ctr Networked Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Univ Seville, Serv Neurol & Neurofisiol, Unidad Trastornos Movimiento,CSIC, Hosp Univ Virgen Rocio,Inst Biomed Sevilla IBiS, Seville, Spain
Calero, M:
Carlos III Inst Hlth, Ctr Networked Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Queen Sofia Fdn, CIEN Fdn, Alzheimer Ctr, Madrid, Spain
Inst Salud Carlos III ISCIII, Madrid, Spain
Medina, M:
Carlos III Inst Hlth, Ctr Networked Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Queen Sofia Fdn, CIEN Fdn, Alzheimer Ctr, Madrid, Spain
Rabano, A:
Carlos III Inst Hlth, Ctr Networked Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Queen Sofia Fdn, CIEN Fdn, Alzheimer Ctr, Madrid, Spain
BT CIEN, Madrid, Spain
Avila, J:
Carlos III Inst Hlth, Ctr Networked Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Univ Autonoma Madrid UAM, Ctr Biol Mol Severo Ochoa CBMSO, Dept Mol Neuropathol, Consejo Super Invest Cient CSIC, Madrid, Spain
Antunez, C:
Hosp Clin Univ Virgen Arrixaca, Unidad Demencias, Madrid, Spain
Real, LM:
Hosp Univ Valme, Unidad Clin Enfermedades Infecciosas & Microbiol, Seville, Spain
Univ Malaga, Sch Med, Dept Surg Biochem & Mol Biol, Malaga, Spain
Orellana, A:
Univ Int Catalunya, Inst Catala Neurociencies Aplicades, Res Ctr & Memory Clin, Fundacio ACE, Barcelona, Spain
Carracedo, A:
Univ Santiago de Compostela, Grp Med Xen, Ctr Nacl Genotipado CEGEN PRB3 ISCIII, Santiago De Compostela, Spain
Fdn Publ Galega Med Xen CIBERER IDIS, Santiago De Compostela, Spain
Saez, ME:
CAEBI Ctr Andaluz Estudios Bioinformat, Seville, Spain
Tarraga, L:
Univ Int Catalunya, Inst Catala Neurociencies Aplicades, Res Ctr & Memory Clin, Fundacio ACE, Barcelona, Spain
Carlos III Inst Hlth, Ctr Networked Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Boada, M:
Univ Int Catalunya, Inst Catala Neurociencies Aplicades, Res Ctr & Memory Clin, Fundacio ACE, Barcelona, Spain
Carlos III Inst Hlth, Ctr Networked Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Cruchaga, C:
Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO USA
Ruiz, A:
Univ Int Catalunya, Inst Catala Neurociencies Aplicades, Res Ctr & Memory Clin, Fundacio ACE, Barcelona, Spain
Carlos III Inst Hlth, Ctr Networked Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Blesa, R.:
Univ Autonoma Barcelona, Hosp Santa Creu & Sant Pau, Dept Neurol, Memory Unit, Barcelona, Spain
Fortea J.:
Univ Autonoma Barcelona, Hosp Santa Creu & Sant Pau, Dept Neurol, Memory Unit, Barcelona, Spain
Lleó A.:
Univ Autonoma Barcelona, Hosp Santa Creu & Sant Pau, Dept Neurol, Memory Unit, Barcelona, Spain
Vivancos, L.:
Hospital Virgen de la Arrixaca, Murcia, Spain
Green Published, gold, All Open Access, Gold, Green
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