Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer’s disease
Open accessAbstract
By analyzing late-onset Alzheimer's disease (LOAD) in a genome-wide association study (313,504 SNPs, three series, 844 cases and 1,255 controls) and evaluating the 25 SNPs with the most significant allelic association in four additional series (1,547 cases and 1,209 controls), we identified a SNP (rs5984894) on Xq21.3 in PCDH11X that is strongly associated with LOAD in individuals of European descent from the United States. Analysis of rs5984894 by multivariable logistic regression adjusted for sex gave global P values of 5.7 x 10(-5) in stage 1, 4.8 x 10(-6) in stage 2 and 3.9 x 10(-12) in the combined data. Odds ratios were 1.75 (95% CI = 1.42-2.16) for female homozygotes (P = 2.0 x 10(-7)) and 1.26 (95% CI = 1.05-1.51) for female heterozygotes (P = 0.01) compared to female noncarriers. For male hemizygotes (P = 0.07) compared to male noncarriers, the odds ratio was 1.18 (95% CI = 0.99-1.41).
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Prior genome-wide association studies of AD all identified strong evidence for association to APOE but less convincing evidence implicating other genes.
“All have identified strong evidence for association to APOE, but less convincing evidence implicating other genes2 -9 .”
From Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease (2009) · cites this paper as [5]
The paper reports that only APOE-linked SNPs reached genome-wide significance in its stage I GWAS (Methods, Statistical Analyses; page unavailable), supporting the APOE portion. It does not establish that all prior AD GWAS had this pattern, and its combined-stage analysis reports a genome-wide-significant association for a PCDH11X SNP. (LLM, conf=0.83)
Experimental — accuracy not yet measuredSeven of the earliest GWAS, each of which used less than 2,000 cases, identified only APOE as significantly associated with Alzheimer's disease.
“seven of the earliest GWAS, each of which used less than 2,000 cases, identified only APOE as significantly associated with AD [84–90].”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [85]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
PLINK: a tool set for whole-genome association and population-based linkage analyses.
Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A. R., Bender, D., Maller, J., Sklar, P., de Bakker, P. I. W., Daly, M. J., et al. (2007) · The American Journal of Human Genetics · doi:10.1086/519795 · Cited by 34,089 · see citing works
Haploview: analysis and visualization of LD and haplotype maps
Barrett, J., Fry, B., Maller, J., & Daly, M. (2005) · Bioinform. · doi:10.1093/bioinformatics/bth457 · Cited by 15,086 · see citing works
Principal components analysis corrects for stratification in genome-wide association studies
Price, A. L., Patterson, N. J., Plenge, R. M., Weinblatt, M. E., Shadick, N. A., & Reich, D. (2006) · Nature Genetics · doi:10.1038/ng1847 · Cited by 10,248 · see citing works
Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., & Pericak-Vance, M. A. (1993) · Science · doi:10.1126/science.8346443 · Cited by 9,429 · see citing works
Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease
Corder, E. H., Saunders, A. M., Risch, N. J., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Rimmler, J. B., Locke, P. A., Conneally, P. M., Schmader, K. E., et al. (1994) · Nature Genetics · doi:10.1038/ng0694-180 · Cited by 1,920 · see citing works
Role of Genes and Environments for Explaining Alzheimer Disease
Gatz, M., Reynolds, C. A., Fratiglioni, L., Johansson, B., Mortimer, J. A., Berg, S., Fiske, A., & Pedersen, N. L. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.2.168 · Cited by 1,798 · see citing works
Evans, D. A. (1989) · JAMA · doi:10.1001/jama.262.18.2551 · Cited by 1,627 · see citing works
Evans, D. A. (1989) · JAMA · doi:10.1001/jama.1989.03430180093036 · Cited by 1,226 · see citing works
Evans, D. A., Funkenstein, H. H., Albert, M., Scherr, P. A., Cook, N. R., Chown, M. J., Hebert, L. E., Hennekens, C. H., & Taylor, J. O. (1989) · PubMed · Cited by 599 · see citing works
Proteins of the CNR Family Are Multiple Receptors for Reelin
Senzaki, K., Ogawa, M., & Yagi, T. (1999) · Cell · doi:10.1016/s0092-8674(00)81552-4 · Cited by 272 · see citing works
Presenilin-dependent Processing and Nuclear Function of γ-Protocadherins
Haas, I. G., Frank, M., Véron, N., & Kemler, R. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m412909200 · Cited by 141 · see citing works
Conservation of PCDHX in mammals; expression of human X/Y genes predominantly in brain
Blanco, P., Sargent, C. A., Boucher, C. A., et al. (2000) · Mammalian Genome · doi:10.1007/s003350010177 · Cited by 125 · see citing works
Farrer, L. A. (1997) · JAMA · doi:10.1001/jama.1997.03550160069041 · Cited by 124 · cited 1× · see citing works
“Multiple rare mutations in the genes encoding the amyloid β protein precursor, presenilin 1 and presenilin 2 cause an early-onset familial form of Alzheimer's disease with autosomal dominant inheritance, but the only well established susceptibility allele for LOAD is the APOE e4 allel”
BackgroundKim, S., Chung, H. S., Sun, W., & Kim, H. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2007.03.052 · Cited by 120 · see citing works
Williams, N. A., Close, J. P., Giouzeli, M., & Crow, T. J. (2006) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30357 · Cited by 89 · see citing works
Durand, C. M., Kappeler, C., Betancur, C., et al. (2005) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30229 · Cited by 55 · see citing works
Inactivation status of PCDH11X: sexual dimorphisms in gene expression levels in brain
Lopes, A. M., Ross, N., Close, J. P., Dagnall, A., Amorim, A., & Crow, T. J. (2006) · Human Genetics · doi:10.1007/s00439-006-0134-0 · Cited by 53 · see citing works
Blanco, P., Sargent, C. A., & Affara, N. A. (2004) · Mammalian Genome · doi:10.1007/s00335-003-3028-7 · Cited by 30 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Harold, D., Abraham, R., Hollingworth, P., Sims, R., Gerrish, A., Hamshere, M. L., Pahwa, J. S., Moskvina, V., Dowzell, K., Williams, A., et al. (2009) · Nature Genetics · doi:10.1038/ng.440 · Cited by 3,326 · see citing works
Self-citationGenome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease
the European Alzheimer's Disease Initiative Investigators, Lambert, J.-C., Heath, S., Even, G., Campion, D., Sleegers, K., Hiltunen, M., Combarros, O., Zelenika, D., Bullido, M. J., et al. (2009) · Nature Genetics · doi:10.1038/ng.439 · Cited by 2,234 · see citing works
Naj, A. C., Jun, G., Beecham, G. W., Wang, L.-S., Vardarajan, B. N., Buros, J., Gallins, P. J., Buxbaum, J. D., Jarvik, G. P., Crane, P. K., et al. (2011) · Nature Genetics · doi:10.1038/ng.801 · Cited by 1,901 · see citing works
Self-citationEpidemiology of Alzheimer disease
Reitz, C., Brayne, C., & Mayeux, R. (2011) · Nature Reviews Neurology · doi:10.1038/nrneurol.2011.2 · Cited by 1,675 · see citing works
Genome-wide Analysis of Genetic Loci Associated With Alzheimer Disease
Seshadri, S. (2010) · JAMA · doi:10.1001/jama.2010.574 · Cited by 1,219 · see citing works
The Genetics of Alzheimer Disease: Back to the Future
Bertram, L., Lill, C. M., & Tanzi, R. E. (2010) · Neuron · doi:10.1016/j.neuron.2010.10.013 · Cited by 834 · see citing works
Single-nucleus chromatin accessibility and transcriptomic characterization of Alzheimer’s disease
Morabito, S., Miyoshi, E., Michael, N., Shahin, S., Martini, A. C., Head, E., Silva, J., Leavy, K., Perez-Rosendahl, M., & Swarup, V. (2021) · Nature Genetics · doi:10.1038/s41588-021-00894-z · Cited by 643 · see citing works
Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: A Meta-analysis
Neu, S. C., Pa, J., Kukull, W., Beekly, D., Kuzma, A., Gangadharan, P., Wang, L.-S., Romero, K., Arneric, S. P., Redolfi, A., et al. (2017) · JAMA Neurology · doi:10.1001/jamaneurol.2017.2188 · Cited by 674 · see citing works
Reitz, C., Jun, G., Naj, A., Rajbhandary, R., Vardarajan, B. N., Wang, L.-S., Valladares, O., Lin, C.-F., Larson, E. B., Graff-Radford, N. R., et al. (2013) · JAMA · doi:10.1001/jama.2013.2973 · Cited by 431 · see citing works
Self-citationJun, G. (2010) · Archives of Neurology · doi:10.1001/archneurol.2010.201 · Cited by 422 · see citing works
Mechanisms of sex differences in Alzheimer’s disease
Lopez-Lee, C., Torres, E. R. S., Carling, G., & Gan, L. (2024) · Neuron · doi:10.1016/j.neuron.2024.01.024 · Cited by 376 · see citing works
Genome-wide association studies in Alzheimer’s disease
Bertram, L., & Tanzi, R. E. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp406 · Cited by 257 · see citing works
Genetics of familial and sporadic Alzheimer s disease
Piaceri, I. (2013) · Frontiers in Bioscience · doi:10.2741/e605 · Cited by 256 · see citing works
Finch, N., Carrasquillo, M. M., Baker, M., Rutherford, N. J., Coppola, G., DeJesus-Hernandez, M., Crook, R., Hunter, T., Ghidoni, R., Benussi, L., et al. (2011) · Neurology · doi:10.1212/wnl.0b013e31820a0e3b · Cited by 243 · see citing works
Self-citationIs Alzheimer’s disease a systemic disease?
Morris, J. K., Honea, R. A., Vidoni, E. D., Swerdlow, R. H., & Burns, J. M. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2014.04.012 · Cited by 219 · see citing works
Replication of CLU, CR1, and PICALM Associations With Alzheimer Disease
Carrasquillo, M. M., Belbin, O., Hunter, T. A., Ma, L., Bisceglio, G. D., Zou, F., Crook, J. E., Pankratz, V. S., Dickson, D. W., Graff-Radford, N. R., et al. (2010) · Archives of Neurology · doi:10.1001/archneurol.2010.147 · Cited by 208 · see citing works
Self-citationLee, J. H., Cheng, R., Barral, S., Reitz, C., Medrano, M., Lantigua, R., Jiménez-Velazquez, I. Z., Rogaeva, E., St. George-Hyslop, P. H., & Mayeux, R. (2011) · Archives of Neurology · doi:10.1001/archneurol.2010.292 · Cited by 190 · see citing works
Evolution of genetic and genomic features unique to the human lineage
O'Bleness, M., Searles, V. B., Varki, A., Gagneux, P., & Sikela, J. M. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3336 · Cited by 168 · see citing works
Conserved brain myelination networks are altered in Alzheimer’s and other neurodegenerative diseases
Allen, M., Wang, X., Burgess, J. D., Watzlawik, J., Serie, D. J., Younkin, C. S., Nguyen, T., Malphrus, K. G., Lincoln, S., Carrasquillo, M. M., et al. (2018) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2017.09.012 · Cited by 143 · see citing works
Self-citationRegulation of neural circuit formation by protocadherins
Peek, S. L., Mah, K. M., & Weiner, J. A. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2572-3 · Cited by 119 · see citing works
The pursuit of susceptibility genes for Alzheimer's disease: progress and prospects
Sleegers, K., Lambert, J.-C., Bertram, L., Cruts, M., Amouyel, P., & Van Broeckhoven, C. (2010) · Trends in Genetics · doi:10.1016/j.tig.2009.12.004 · Cited by 129 · see citing works
Genetic architecture of Alzheimer's disease
Neuner, S. M., TCW, J., & Goate, A. M. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104976 · Cited by 126 · see citing works
“In fact, seven of the earliest GWAS, each of which used less than 2000 cases, identified only APOE as significantly associated with AD (Feulner et al., 2010; Carrasquillo et al., 2009; Beecham et al., 2009; Bertram et al., 2008; Li et al., 2008; Abraham et al., 2008; Liu et al., 2007).”
BackgroundGenome-wide association analysis of age-at-onset in Alzheimer's disease
Kamboh, M. I., Barmada, M. M., Demirci, F. Y., Minster, R. L., Carrasquillo, M. M., Pankratz, V. S., Younkin, S. G., Saykin, A. J., Initiative, T. A. D. N., Sweet, R. A., et al. (2012) · Molecular Psychiatry · doi:10.1038/mp.2011.135 · Cited by 100 · see citing works
Self-citationMaternal transmission of Alzheimer's disease: prodromal metabolic phenotype and the search for genes
Mosconi, L., Berti, V., Swerdlow, R. H., Pupi, A., Duara, R., & de Leon, M. (2010) · Human Genomics · doi:10.1186/1479-7364-4-3-170 · Cited by 85 · see citing works
The association of angiotensin-converting enzyme with biomarkers for Alzheimer’s disease
Jochemsen, H. M., Teunissen, C. E., Ashby, E. L., van der Flier, W. M., Jones, R. E., Geerlings, M. I., Scheltens, P., Kehoe, P. G., & Muller, M. (2014) · Alzheimer's Research & Therapy · doi:10.1186/alzrt257 · Cited by 77 · see citing works
Peterson, D., Munger, C., Crowley, J., Corcoran, C., Cruchaga, C., Goate, A. M., Norton, M. C., Green, R. C., Munger, R. G., Breitner, J. C. S., et al. (2014) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2013.02.010 · Cited by 44 · see citing works
Yates, S. C., Zafar, A., Rabai, E. M., Foxall, J. B., Nagy, S., Morrison, K. E., Clarke, C., Esiri, M. M., Christie, S., Smith, A. D., et al. (2015) · PLOS ONE · doi:10.1371/journal.pone.0114050 · Cited by 31 · see citing works
Oh, D. J., Bae, J. B., Lipnicki, D. M., Han, J. W., Sachdev, P. S., Kim, T. H., Kwak, K. P., Kim, B. J., Kim, S. G., Kim, J. L., et al. (2023) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.13561 · Cited by 8 · see citing works
PLCG2 as a Risk Factor for Alzheimer's Disease.
Tsai, A. P., Dong, C., Preuss, C., Moutinho, M., Lin, P. B.-C., Hajicek, N., Sondek, J., Bissel, S. J., Oblak, A. L., Carter, G. W., et al. (2020) · doi:10.21203/rs.3.rs-38216/v1 · Cited by 7 · see citing works
- Authors
- Carrasquillo, M. M., Zou, F., Pankratz, V. S., Wilcox, S. L., Ma, L., Walker, L. P., Younkin, S. G., Younkin, C. S., Younkin, L. H., Bisceglio, G. D., Ertekin-Taner, N., Crook, J. E., Dickson, D. W., Petersen, R. C., Graff-Radford, N. R., & Younkin, S. G.
- Affiliations
- Mayo Clinic (US)
- Corresponding author
- Younkin, Samuel G
- Younkin, Steven G
- ORCID
- Venue
- Nature Genetics
- Published
- 2009-01-11
- Volume
- 41
- Issue
- 2
- Pages
- 192-198
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC2873177
- OpenAlex
- W2033552121
- Cited by
- 296
- References
- 18
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 8 · 2023: 9 · 2022: 10 · 2021: 11 · 2020: 13 · 2019: 10 · 2018: 8 · 2017: 13 · 2016: 14 · 2015: 15 · 2014: 15 · 2013: 17 · 2012: 25
- FWCI
- 32.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
- Hirosaki University Repository for Academic Resources (Hirosaki University) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institute on Aging (U01 AG 06576, P50‐AG16574, AG03949, R01AG018023, U01AG006786, P01AG003949, AG 25711, R01-AG18023, AG12716, U24 AG21886, P50AG025711, P01AG017216, F32AG020903, U24AG021886, P50AG016574)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- late-onset Alzheimer's disease, protocadherins, X chromosome, genetic susceptibility, single nucleotide polymorphisms, sex differences, hemizygosity, European ancestry
- MeSH terms
- Protocadherins, Aged, Aged, 80 and over, Alzheimer Disease, Female, Gene Frequency, Heterozygote, Humans, Male, Middle Aged, Genetic Variation, Linkage Disequilibrium, Cadherins, Case-Control Studies, Age of Onset, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
