Genome‐wide linkage analyses of non‐Hispanic white families identify novel loci for familial late‐onset Alzheimer's disease
Open accessAbstract
Introduction: Few high penetrance variants that explain risk in late‐onset Alzheimer's disease (LOAD) families have been found. Methods: We performed genome‐wide linkage and identity‐by‐descent (IBD) analyses on 41 non‐Hispanic white families exhibiting likely dominant inheritance of LOAD, and having no mutations at known familial Alzheimer's disease (AD) loci, and a low burden of APOE ε4 alleles. Results: Two‐point parametric linkage analysis identified 14 significantly linked regions, including three novel linkage regions for LOAD (5q32, 11q12.2–11q14.1, and 14q13.3), one of which replicates a genome‐wide association LOAD locus, the MS4A6A‐MS4A4E gene cluster at 11q12.2. Five of the 14 regions (3q25.31, 4q34.1, 8q22.3, 11q12.2–14.1, and 19q13.41) are supported by strong multipoint results (logarithm of odds [LOD*] ≥1.5). Nonparametric multipoint analyses produced an additional significant locus at 14q32.2 (LOD* = 4.18). The 1‐LOD confidence interval for this region contains one gene, C14orf177, and the microRNA Mir_320, whereas IBD analyses implicates an additional gene BCL11B, a regulator of brain‐derived neurotrophic signaling, a pathway associated with pathogenesis of several neurodegenerative diseases. Discussion: Examination of these regions after whole‐genome sequencing may identify highly penetrant variants for familial LOAD.
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The contribution of rare variants to AD cannot be adequately assessed by GWAS.
“As mentioned above, the contribution of rare variants to AD cannot be adequately assessed by GWAS, although improved imputation methods are being developed to address this limitation [128].”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [128]
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“2 is a 0.78-Mbp segment between map positions 98.81 Mbp and 99.59 Mbp and contains one gene (C14orf177) and one microRNA (miRNA), Mir_320 according to the University of California, Santa Cruz Genes Track [30].”
BackgroundMethodInfluentialPrincipal components analysis corrects for stratification in genome-wide association studies
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“Allele frequencies for all SNPs were based on CEU HapMap data [22].”
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“A check of our linked SNPs in these regions for association with LOAD in the International Genomics of Alzheimer’s Project GWAS summary statistics found no significant associations after correction for multiple testing (P 5! 10(28); Supplementary Table 4) [1].”
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MethodInfluential<i>TREM2</i> Variants in Alzheimer's Disease
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Self-citationVariant of <i>TREM2</i> Associated with the Risk of Alzheimer's Disease
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BackgroundAllele-sharing models: LOD scores and accurate linkage tests.
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“BCL11B is thought to primarily reduce BDNF signaling [40], consistent with observations that BDNF serum and expression levels are decreased in AD [41,44,45] and high BDNF levels protect against AD [46,47].”
BackgroundBrain-derived neurotrophic factor in neurodegenerative diseases
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BackgroundBrain-derived neurotrophic factor is reduced in Alzheimer's disease
Connor, B., Young, D., Yan, Q., Faull, R. L. M., Synek, B., & Dragunow, M. (1997) · Molecular Brain Research · doi:10.1016/s0169-328x(97)00125-3 · Cited by 581 · see citing works
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BackgroundSerum Brain-Derived Neurotrophic Factor and the Risk for Dementia: The Framingham Heart Study
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“with risk for amyotrophic lateral sclerosis [33] and lipoprotein cholesterol levels [34], whereas members of the mir-320 miRNA family are significantly altered in sporadic AD brains [35] and associated with both neurite outgrowth [36] and neurodegeneration [37].”
BackgroundIdentification of Novel Genes in Late-Onset Alzheimer's Disease
Pericak‐Vance, M. A., Grubber, J. M., Bailey, L., Hedges, D. J., West, S. G., Santoro, L., Kemmerer, B., Hall, J. L., Saunders, A. M., Roses, A. D., et al. (2000) · Experimental Gerontology · doi:10.1016/s0531-5565(00)00196-0 · Cited by 195 · see citing works
Self-citationSerum Brain-Derived Neurotrophic Factor Levels in Different Neurological Diseases
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“A recent neuroimaging study implicated a role for BDNF in cognitive decline in LOAD patients [48], although AD genetic association studies of BDNF yielded conflicting results [44,49].”
BackgroundResultA Genomewide Screen for Late-Onset Alzheimer Disease in a Genetically Isolated Dutch Population
Liu, F., Arias-Vásquez, A., Sleegers, K., Aulchenko, Y. S., Kayser, M., Sanchez-Juan, P., Feng, B.-J., Bertoli-Avella, A. M., van Swieten, J., Axenovich, T. I., et al. (2007) · The American Journal of Human Genetics · doi:10.1086/518720 · Cited by 156 · see citing works
Analyses of the National Institute on Aging Late-Onset Alzheimer's Disease Family Study
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Self-citationA dual function of Bcl11b/Ctip2 in hippocampal neurogenesis
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“BCL11B is predominantly expressed in striatal neurons and may play an important role in adult neurogenesis [42], a process that when dysregulated may lead to AD [43].”
BackgroundLinkage Analysis in the Next-Generation Sequencing Era
Bailey-Wilson, J., & Wilson, A. F. (2011) · Human Heredity · doi:10.1159/000334381 · Cited by 112 · cited 1× · see citing works
“Linkage analysis in large multiplex pedigrees is a robust approach for identifying disease loci in the presence of allelic heterogeneity, and thus can be valuable for targeting regions for sequencing studies [8].”
BackgroundGene therapy in Alzheimer’s disease – potential for disease modification
Nilsson, P., Iwata, N., Muramatsu, S., Tjernberg, L. O., Winblad, B. G., & Saido, T. C. (2010) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2010.01038.x · Cited by 96 · cited 1× · see citing works
“Finally, it has been suggested that BDNF-based drugs might be effective therapies for AD and other neurodegenerative diseases [50], with targeting ofBCL11B interactionswith BDNFeven being suggested as a feasible therapeutic approach to elevate BDNF signaling in neurodegenerative drug development [40].”
BackgroundEvidence for a Novel Late-Onset Alzheimer Disease Locus on Chromosome 19p13.2
Wijsman, E. M., Daw, E. W., Yu, C. E., Payami, H., Steinbart, E. J., Nochlin, D., Conlon, E. M., Bird, T. D., & Schellenberg, G. D. (2004) · The American Journal of Human Genetics · doi:10.1086/423393 · Cited by 95 · see citing works
Self-citationLinkage probability and its approximate confidence interval under possible heterogeneity
Ott, J. (1986) · Genetic epidemiology. Supplement · doi:10.1002/gepi.1370030739 · Cited by 80 · cited 2×
“The resulting 1-LOD region [17] at 14q32.”
MethodPopulation genetics of rare variants and complex diseases
Maher, M. C., Uricchio, L. H., Torgerson, D., & Hernandez, R. D. (2013) · Human Heredity · doi:10.1159/000346826 · Cited by 73 · cited 1× · see citing works
“It is likely that rare variants contribute to complex disease, however [3], and recent reports implicating rare variants in PLD3, APP, and TREM2 [4–7] support their involvement in both sporadic and familial LOAD.”
BackgroundOf mice and men: neurogenesis, cognition and Alzheimer’s disease
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“BCL11B is predominantly expressed in striatal neurons and may play an important role in adult neurogenesis [42], a process that when dysregulated may lead to AD [43].”
BackgroundWu, W., Iwata, S., Homma, S., Worman, H., & Muchir, A. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddt387 · Cited by 67 · see citing works
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“A recent neuroimaging study implicated a role for BDNF in cognitive decline in LOAD patients [48], although AD genetic association studies of BDNF yielded conflicting results [44,49].”
ResultSelf-citationCorrecting for multiple analyses in genomewide linkage studies
Camp, N., & Farnham, J. (2001) · Annals of Human Genetics · doi:10.1046/j.1469-1809.2001.6560577.x · Cited by 62 · cited 2× · see citing works
“9! 10(25)) in LOD score analyses of densemarker genome-wide linkage scans and approximates a level suggested by Camp and Farnham [24] for testing of two independent two-point models.”
BackgroundTang, B., Lena, P. D., Schaffer, L., Head, S., Baldi, P., & Thomas, E. (2011) · PLoS ONE · doi:10.1371/journal.pone.0023691 · Cited by 61 · cited 3× · see citing works
“BCL11B is thought to primarily reduce BDNF signaling [40], consistent with observations that BDNF serum and expression levels are decreased in AD [41,44,45] and high BDNF levels protect against AD [46,47].”
BackgroundAnalysis of genome-wide copy number variation in Irish and Dutch ALS populations.
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“with risk for amyotrophic lateral sclerosis [33] and lipoprotein cholesterol levels [34], whereas members of the mir-320 miRNA family are significantly altered in sporadic AD brains [35] and associated with both neurite outgrowth [36] and neurodegeneration [37].”
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“with risk for amyotrophic lateral sclerosis [33] and lipoprotein cholesterol levels [34], whereas members of the mir-320 miRNA family are significantly altered in sporadic AD brains [35] and associated with both neurite outgrowth [36] and neurodegeneration [37].”
BackgroundRamirez, A., van der Flier, W. M., Herold, C., Ramonet, D., Heilmann, S., Lewczuk, P., Popp, J., Lacour, A., Drichel, D., Louwersheimer, E., et al. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu372 · Cited by 49 · see citing works
Self-citationMicroRNA-320 Induces Neurite Outgrowth by Targeting ARPP-1
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“with risk for amyotrophic lateral sclerosis [33] and lipoprotein cholesterol levels [34], whereas members of the mir-320 miRNA family are significantly altered in sporadic AD brains [35] and associated with both neurite outgrowth [36] and neurodegeneration [37].”
BackgroundCummings, A., Jiang, L., Edwards, D. V., Mccauley, J., Laux, R., McFarland, L. L., Fuzzell, D., Knebusch, C., Caywood, L., Reinhart‐Mercer, L., et al. (2012) · Annals of Human Genetics · doi:10.1111/j.1469-1809.2012.00721.x · Cited by 46 · see citing works
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“A recent neuroimaging study implicated a role for BDNF in cognitive decline in LOAD patients [48], although AD genetic association studies of BDNF yielded conflicting results [44,49].”
ResultA familial case of Alzheimer's disease without tau pathology may be linked with chromosome 3 markers
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“1) [52] and in a genomewide linkage study of Dutch families (LOD 5 4.”
BackgroundAge-at-onset linkage analysis in Caribbean Hispanics with familial late-onset Alzheimer’s disease
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“60) has been reported at 14q32 in an AAO linkage analysis in Hispanic LOAD families [32].”
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“A combined association and linkage analysis of all markers in this region using CAPL [51] produced no suggestive or significantly associated SNPs (data not shown).”
Self-citationOlorin: combining gene flow with exome sequencing in large family studies of complex disease
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“IBD segments were determined by estimating haplotypes in MERLIN followed by identification of IBD sharing regions using Olorin [25].”
MethodPowerTrim: An automated decision support algorithm for preprocessing family-based genetic data.
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MethodSelf-citationLONGITUDINAL FOLLOW-UP OF LATE-ONSET ALZHEIMER DISEASE FAMILIES
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“As mentioned above, the contribution of rare variants to AD cannot be adequately assessed by GWAS, although improved imputation methods are being developed to address this limitation (Kunkle et al., 2016).”
BackgroundSelf-citationBcl11b—A Critical Neurodevelopmental Transcription Factor—Roles in Health and Disease
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Self-citationSimino, J. M., Wang, Z., Bressler, J., Chouraki, V. A., Yang, Q., Younkin, S. G., Seshadri, S. S., Fornage, M., Boerwinkle, E., & Mosley, T. H. (2017) · PLoS ONE · doi:10.1371/journal.pone.0180046 · Cited by 20 · see citing works
Rare genetic variation implicated in non-Hispanic white families with Alzheimer disease
Beecham, G., Vardarajan, B., Blue, E., Bush, W., Jaworski, J., Barral, S., Destefano, A., Hamilton-Nelson, K., Kunkle, B. W., Martin, E., et al. (2018) · Neurology: Genetics · doi:10.1212/nxg.0000000000000286 · Cited by 25 · see citing works
“Nonparametric analyses are described in detail elsewhere.(19) For parametric multipoint Table 1 Priority variants from consensus linkage regions”
MethodSelf-citationZhang, M., Shi, Y.-D., & Jiang, H.-Y. (2022) · International Journal of Colorectal Disease · doi:10.1007/s00384-022-04131-9 · Cited by 23 · see citing works
“A recent genome-wide pleiotropic analysis reported that IBD and dementia shared BCL11B alleles [10], suggesting a genetic basis for their clinical co-occurrence.”
BackgroundAlzheimer’s disease basics: we all should know
Das, S. K. (2025) · Neurological Research · doi:10.1080/01616412.2025.2529560 · Cited by 19 · see citing works
Regulation of hippocampal mossy fiber-CA3 synapse function by a Bcl11b/C1ql2/Nrxn3(25b+) pathway
Koumoundourou, A., Rannap, M., Bruyckere, E. D., Nestel, S., Reissner, C., Egorov, A. V., Liu, P.-T., Missler, M., Heimrich, B., Draguhn, A., et al. (2023) · bioRxiv · doi:10.7554/elife.89854 · Cited by 16 · see citing works
“The transcription factor Bcl11b has been linked to neuro-developmental ( Lessel et al., 2018 ), neurodegenerative ( Kunkle et al., 2016 ; Song et al., 2022 ) and neuropsychiatric disorders ( Whitton et al., 2018 ; Whitton et al., 2016 ).”
BackgroundTosto, G., & Reitz, C. (2016) · Molecular and Cellular Probes · doi:10.1016/j.mcp.2016.09.001 · Cited by 14 · see citing works
Roe, C., Babulal, G., Mishra, S., Gordon, B., Stout, S. H., Ott, B. L., Carr, D., Ances, B., Morris, J., & Benzinger, T. (2017) · Journal of Alzheimer's Disease · doi:10.3233/jad-170521 · Cited by 15 · see citing works
Uechi, L., Jalali, M., Wilbur, J., French, J. L., Jumbe, N., Meaney, M., Gluckman, P., Karnani, N., Sakhanenko, N. A., & Galas, D. (2020) · PLoS ONE · doi:10.1371/journal.pone.0242684 · Cited by 13 · see citing works
Cheng, R., Tang, M., Martinez, I. M., Ayodele, T., Baez, P., Reyes‐Dumeyer, D., Lantigua, R., Medrano, M. Z., Jiménez‐Velázquez, I. Z., Lee, J. H., et al. (2018) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1016/j.dadm.2018.07.007 · Cited by 11 · see citing works
“Parametric multipoint analysis was performed on regions previously reported in the Alzheimer’s Disease Sequencing Project [33,34] but not identified in the parametric two-point models in this sample (2q22, 3q13, 4q34, 5p13, 6q25, 7p14, 7p21, 8q22, 9p22, 9q33, 10p13, 11q12, 13q14, 14q13, 19q13).”
MethodSelf-citationGenetic Complexity of Early-Onset Alzheimer’s Disease
Ghani, M., Reitz, C., George-Hyslop, P. S. S., & Rogaeva, E. (2018) · Springer eBooks · doi:10.1007/978-3-319-72938-1_3 · Cited by 11 · see citing works
Involvement of transposable elements in Alzheimer’s disease pathogenesis
Mustafin, R., & Khusnutdinova, E. (2024) · Vavilovskii zhurnal genetiki i selektsii · doi:10.18699/vjgb-24-27 · Cited by 8 · see citing works
Vertical stratification of K uptake for soybean-based crop rotation
de Oliveira, S. M., Dias, D. S., Reis, A. F. D. B., Cruz, S. C. S., & Favarin, J. L. (2020) · Nutrient Cycling in Agroecosystems · doi:10.1007/s10705-020-10059-9 · Cited by 7
“To deal with K losses, specially leaching, the concept of cycling soil nutrients throughout cover crop has previously been investigated (Fageria et al. 2005; Garcia et al. 2008; Smil 2018).”
BackgroundAncestral Genomic Functional Differences in Oligodendroglia: Implications for Alzheimer’s DiseasePreprint
Ramirez, A., Bertholim-Nasciben, L., Moura, S., Coombs, L. E., Rajabli, F., DeRosa, B., Whitehead, P., Adams, L., Starks, T. D., Mena, P., et al. (2024) · Research Square · doi:10.21203/rs.3.rs-5338140/v1 · Cited by 4 · see citing works
Self-citationXia, R., Jian, X., Rodrigue, A., Bressler, J., Boerwinkle, E., Cui, B.-Q., Daviglus, M., Decarli, C., Gallo, L., Glahn, D., et al. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.14082 · Cited by 1 · see citing works
Nuytemans, K., Rajabli, F., Jean-Francois, M. N., Kurup, J., Adams, L., Starks, T. D., Whitehead, P., Kunkle, B. W., Caban-Holt, A., Haines, J., et al. (2023) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2023.10.010 · Cited by 1 · see citing works
Self-citationRelationship of Retroelements with Antiviral Proteins and Epigenetic Factors in Alzheimer's Disease
Mustafin, R. (2024) · OBM Neurobiology · doi:10.21926/obm.neurobiol.2404252
Using Tweetchats to Build Community Awareness and Advocacy around Alzheimer’s Disease for Latinos
Sukumaran, P., Chalela, P., Aguilar, R. P., Despres, C., Mcalister, A., & Ramirez, A. (2021) · Journal of health communication · doi:10.1080/10810730.2021.1927258
“5 times more likely to develop Alzheimer’s disease than White non-Latinos (Cox & Monk, 1993; Kunkle et al., 2016; Reitz & Mayeux, 2014).”
BackgroundLarge Artery Stiffness: Genes and Pathways
Maskari, R. A. (2018) · doi:10.17863/cam.25210
“novel causal gene [274], most likely attributable to its transcriptional regulation of BDNF whose levels are reduced in the brains of Alzheimer’s patients [275].”
BackgroundGenetics of Alzheimer's disease: an update
Tang, M., & Reitz, C. (2017) · Future Neurology · doi:10.2217/fnl-2017-0003
- Authors
- Kunkle, B. W., Jaworski, J., Barral, S., Vardarajan, B., Beecham, G. W., Martin, E. R., Cantwell, L. S., Partch, A., Bird, T. D., Raskind, W. H., DeStefano, A. L., Carney, R. M., Cuccaro, M., Vance, J. M., Farrer, L. A., Goate, A. M., Foroud, T., Mayeux, R. P., Schellenberg, G. D., Haines, J. L., & Pericak‐Vance, M. A.
- Affiliations
- University of Miami (US)
- Columbia University Irving Medical Center (US)
- Washington University in St. Louis (US)
- University of Pennsylvania (US)
- University of Washington (US)
- Boston University (US)
- John P. Hussman Institute for Human Genomics, Miller School of Medicine University of Miami Miami FL USA
- Indiana University Indianapolis (US)
- Case Western Reserve University (US)
- Corresponding author
- Pericak‐Vance, Margaret A.
- ORCID
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2015-09-10
- Volume
- 12
- Issue
- 1
- Pages
- 2-10
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- PMC
- PMC4717829
- OpenAlex
- W1632374221
- Cited by
- 32
- References
- 54
- Citations by year
- 2025: 2 · 2024: 6 · 2023: 6 · 2022: 1 · 2021: 1 · 2020: 3 · 2018: 4 · 2017: 7 · 2016: 2
- FWCI
- 3.19
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Alzheimer s & Dementia (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by-nc-nd)
- IUScholarWorks (Indiana University) (submittedVersion)
- Purdue University Indianapolis (Indiana University) (submittedVersion)
- Funders
- Alzheimer's Association (IIRG09133827, ADGC–10–196728)
- Labex
- Institut National de la Santé et de la Recherche Médicale
- National Heart, Lung, and Blood Institute (R01 HL105756)
- Hjartavernd
- 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, familial Alzheimer's disease
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Humans, Genetic Linkage, Middle Aged, Pedigree, Genetic Predisposition to Disease, White People, 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.
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