Association of long runs of homozygosity with Alzheimer disease among African American individuals

Mahdi Ghani, Christiane Reitz, Rong Cheng, Badri Narayan Vardarajan, Gyungah Jun, Christine Sato, Adam Naj, Ruchita Rajbhandary, Li San Wang, Otto Valladares, Chiao Feng Lin, Eric B. Larson, Neill R. Graff-Radford, Denis Evans, Philip L. De Jager, Paul K. Crane, Joseph D. Buxbaum, Jill R. Murrell, Towfique Raj, Nilufer Ertekin-Taner & 153 others Mark Logue, Clinton T. Baldwin, Robert C. Green, Lisa L. Barnes, Laura B. Cantwell, M. Daniele Fallin, Rodney C.P. Go, Patrick A. Griffith, Thomas O. Obisesan, Jennifer J. Manly, Kathryn L. Lunetta, M. Ilyas Kamboh, Oscar L. Lopez, David A. Bennett, Hugh Hendrie, Kathleen S. Hall, Alison M. Goate, Goldie S. Byrd, Walter A. Kukull, Tatiana M. Foroud, Jonathan L. Haines, Lindsay A. Farrer, Margaret A. Pericak-Vance, Joseph H. Lee, Gerard D. Schellenberg, Peter St. George-Hyslop, Richard Mayeux, Ekaterina Rogaeva, Marilyn S. Albert, Roger L. Albin, Liana G. Apostolova, Steven E. Arnold, Robert Clinton Barber, Michael M. Barmada, Thomas G. Beach, Gary W. Beecham, Duane Beekly, Eileen H. Bigio, Thomas D. Bird, Deborah Blacker, Bradley F. Boeve, James D. Bowen, Adam Boxer, James R. Burke, Guiqing Cai, Nigel J. Cairns, Chuanhai Cao, Chris S. Carlson, Regina M. Carney, Steven L. Carroll, Helena C. Chui, David G. Clark, David H. Cribbs, Elizabeth A. Crocco, Carlos Cruchaga, Charles DeCarli, Steven T. DeKosky, F. Yesim Demirci, Malcolm Dick, Kelley M. Faber, Kenneth B. Fallon, Steven Ferris, Matthew P. Frosch, Douglas R. Galasko, Mary Ganguli, Marla Gearing, Daniel H. Geschwind, Bernardino Ghetti, John R. Gilbert, Sid Gilman, Jonathan D. Glass, John H. Growdon, Hakon Hakonarson, Ronald L. Hamilton, Kara L. Hamilton-Nelson, Vahram Haroutunian, Lindy E. Harrell, Lawrence S. Honig, Christine M. Hulette, Bradley T. Hyman, Gail P. Jarvik, Gregory A. Jicha, Lee Way Jin, Anna Karydas, John S.K. Kauwe, Jeffrey A. Kaye, Ronald Kim, Edward H. Koo, Neil W. Kowall, Joel H. Kramer, Patricia Kramer, Frank M. LaFerla, James J. Lah, Rosalyn Lang-Walker, James B. Leverenz, Allan I. Levey, Ge Li, Andrew P. Lieberman, Constantine G. Lyketsos, Wendy J. Mack, Daniel C. Marson, Frank Martiniuk, Deborah C. Mash, Eliezer Masliah, Wayne C. McCormick, Susan M. McCurry, Andrew N. McDavid, Ann C. McKee, Marsel Mesulam, Bruce L. Miller, Carol A. Miller, Joshua W. Miller, Thomas J. Montine, John C. Morris, John M. Olichney, Joseph E. Parisi, Elaine Peskind, Ronald C. Petersen, Aimee Pierce, Wayne W. Poon, Huntington Potter, Joseph F. Quinn, Ashok Raj, Murray Raskind, Eric M. Reiman, Barry Reisberg, John M. Ringman, Erik D. Roberson, Mary Sano, Andrew J. Saykin, Julie A. Schneider, Lon S. Schneider, William W. Seeley, Amanda G. Smith, Joshua A. Sonnen, Salvatore Spina, Robert A. Stern, Rudolph E. Tanzi, John Q. Trojanowski, Juan C. Troncoso, Debby W. Tsuang, Vivianna M. Van Deerlin, Linda J. Van Eldik, Harry V. Vinters, Jean Paul Vonsattel, Sandra Weintraub, Kathleen A. Welsh-Bohmer, Jennifer Williamson, Randall L. Woltjer, Clinton B. Wright, Steven G. Younkin, Chang En Yu, Lei Yu

Research output: Contribution to journalArticleResearchpeer-review

14 Citations (Scopus)

Abstract

IMPORTANCE: Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3%of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays. OBJECTIVE: To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals. DESIGN, SETTING, AND PARTICIPANTS: Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-basedROHmeasurementswere analyzed using rawor imputed genotype data.We studied the rawgenotypes from 2 case-control subsets grouped based on SNP array: Alzheimer's Disease Genetics Consortium data set (871 cases and 1620control individuals) and Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals).We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals. MAIN OUTCOMES AND MEASURES: The ROHs larger than 1Mb, 2Mb, or 3Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses. RESULTS: The African American cohort had a lowdegree of inbreeding (F × 0.006). In the Alzheimer's Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2Mb (P =.004) or greater than 3Mb (P =.02), aswell as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 =.04; ROHs >2 Mb). In the Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 =.02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 =.03; ROHs >3 Mb). Atotal of 43 of 49 nominally significant genescommonfor both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs >1Mb in cases vs 12.11 in controls; 2.986Mb average size of ROHs >2Mb in cases vs 2.889Mb in controls; and 22%of cases with ROHs >3Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2 =.006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 =.01; ROHs >1 Mb), encoding a protein from the Claudin family, members of whichwere previously suggested as ADbiomarkers. CONCLUSIONS AND RELEVANCE: To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals.

Original languageEnglish
Pages (from-to)1313-1323
Number of pages11
JournalJAMA Neurology
Volume72
Issue number11
DOIs
StatePublished - 1 Nov 2015

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African Americans
Alzheimer Disease
Single Nucleotide Polymorphism
Consensus
Dementia
Genotype
Claudins
Genes
Mutation
Inbreeding
Datasets
Health
Multigene Family
Haplotypes
Population
Case-Control Studies
Genome
Phenotype

Cite this

Ghani, M., Reitz, C., Cheng, R., Vardarajan, B. N., Jun, G., Sato, C., ... Yu, L. (2015). Association of long runs of homozygosity with Alzheimer disease among African American individuals. JAMA Neurology, 72(11), 1313-1323. https://doi.org/10.1001/jamaneurol.2015.1700
Ghani, Mahdi ; Reitz, Christiane ; Cheng, Rong ; Vardarajan, Badri Narayan ; Jun, Gyungah ; Sato, Christine ; Naj, Adam ; Rajbhandary, Ruchita ; Wang, Li San ; Valladares, Otto ; Lin, Chiao Feng ; Larson, Eric B. ; Graff-Radford, Neill R. ; Evans, Denis ; De Jager, Philip L. ; Crane, Paul K. ; Buxbaum, Joseph D. ; Murrell, Jill R. ; Raj, Towfique ; Ertekin-Taner, Nilufer ; Logue, Mark ; Baldwin, Clinton T. ; Green, Robert C. ; Barnes, Lisa L. ; Cantwell, Laura B. ; Fallin, M. Daniele ; Go, Rodney C.P. ; Griffith, Patrick A. ; Obisesan, Thomas O. ; Manly, Jennifer J. ; Lunetta, Kathryn L. ; Kamboh, M. Ilyas ; Lopez, Oscar L. ; Bennett, David A. ; Hendrie, Hugh ; Hall, Kathleen S. ; Goate, Alison M. ; Byrd, Goldie S. ; Kukull, Walter A. ; Foroud, Tatiana M. ; Haines, Jonathan L. ; Farrer, Lindsay A. ; Pericak-Vance, Margaret A. ; Lee, Joseph H. ; Schellenberg, Gerard D. ; St. George-Hyslop, Peter ; Mayeux, Richard ; Rogaeva, Ekaterina ; Albert, Marilyn S. ; Albin, Roger L. ; Apostolova, Liana G. ; Arnold, Steven E. ; Barber, Robert Clinton ; Barmada, Michael M. ; Beach, Thomas G. ; Beecham, Gary W. ; Beekly, Duane ; Bigio, Eileen H. ; Bird, Thomas D. ; Blacker, Deborah ; Boeve, Bradley F. ; Bowen, James D. ; Boxer, Adam ; Burke, James R. ; Cai, Guiqing ; Cairns, Nigel J. ; Cao, Chuanhai ; Carlson, Chris S. ; Carney, Regina M. ; Carroll, Steven L. ; Chui, Helena C. ; Clark, David G. ; Cribbs, David H. ; Crocco, Elizabeth A. ; Cruchaga, Carlos ; DeCarli, Charles ; DeKosky, Steven T. ; Demirci, F. Yesim ; Dick, Malcolm ; Faber, Kelley M. ; Fallon, Kenneth B. ; Ferris, Steven ; Frosch, Matthew P. ; Galasko, Douglas R. ; Ganguli, Mary ; Gearing, Marla ; Geschwind, Daniel H. ; Ghetti, Bernardino ; Gilbert, John R. ; Gilman, Sid ; Glass, Jonathan D. ; Growdon, John H. ; Hakonarson, Hakon ; Hamilton, Ronald L. ; Hamilton-Nelson, Kara L. ; Haroutunian, Vahram ; Harrell, Lindy E. ; Honig, Lawrence S. ; Hulette, Christine M. ; Hyman, Bradley T. ; Jarvik, Gail P. ; Jicha, Gregory A. ; Jin, Lee Way ; Karydas, Anna ; Kauwe, John S.K. ; Kaye, Jeffrey A. ; Kim, Ronald ; Koo, Edward H. ; Kowall, Neil W. ; Kramer, Joel H. ; Kramer, Patricia ; LaFerla, Frank M. ; Lah, James J. ; Lang-Walker, Rosalyn ; Leverenz, James B. ; Levey, Allan I. ; Li, Ge ; Lieberman, Andrew P. ; Lyketsos, Constantine G. ; Mack, Wendy J. ; Marson, Daniel C. ; Martiniuk, Frank ; Mash, Deborah C. ; Masliah, Eliezer ; McCormick, Wayne C. ; McCurry, Susan M. ; McDavid, Andrew N. ; McKee, Ann C. ; Mesulam, Marsel ; Miller, Bruce L. ; Miller, Carol A. ; Miller, Joshua W. ; Montine, Thomas J. ; Morris, John C. ; Olichney, John M. ; Parisi, Joseph E. ; Peskind, Elaine ; Petersen, Ronald C. ; Pierce, Aimee ; Poon, Wayne W. ; Potter, Huntington ; Quinn, Joseph F. ; Raj, Ashok ; Raskind, Murray ; Reiman, Eric M. ; Reisberg, Barry ; Ringman, John M. ; Roberson, Erik D. ; Sano, Mary ; Saykin, Andrew J. ; Schneider, Julie A. ; Schneider, Lon S. ; Seeley, William W. ; Smith, Amanda G. ; Sonnen, Joshua A. ; Spina, Salvatore ; Stern, Robert A. ; Tanzi, Rudolph E. ; Trojanowski, John Q. ; Troncoso, Juan C. ; Tsuang, Debby W. ; Van Deerlin, Vivianna M. ; Van Eldik, Linda J. ; Vinters, Harry V. ; Vonsattel, Jean Paul ; Weintraub, Sandra ; Welsh-Bohmer, Kathleen A. ; Williamson, Jennifer ; Woltjer, Randall L. ; Wright, Clinton B. ; Younkin, Steven G. ; Yu, Chang En ; Yu, Lei. / Association of long runs of homozygosity with Alzheimer disease among African American individuals. In: JAMA Neurology. 2015 ; Vol. 72, No. 11. pp. 1313-1323.
@article{f7a00deadd3f4b709a47259e5532c559,
title = "Association of long runs of homozygosity with Alzheimer disease among African American individuals",
abstract = "IMPORTANCE: Mutations in known causal Alzheimer disease (AD) genes account for only 1{\%} to 3{\%}of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays. OBJECTIVE: To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals. DESIGN, SETTING, AND PARTICIPANTS: Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-basedROHmeasurementswere analyzed using rawor imputed genotype data.We studied the rawgenotypes from 2 case-control subsets grouped based on SNP array: Alzheimer's Disease Genetics Consortium data set (871 cases and 1620control individuals) and Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals).We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals. MAIN OUTCOMES AND MEASURES: The ROHs larger than 1Mb, 2Mb, or 3Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses. RESULTS: The African American cohort had a lowdegree of inbreeding (F × 0.006). In the Alzheimer's Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2Mb (P =.004) or greater than 3Mb (P =.02), aswell as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 =.04; ROHs >2 Mb). In the Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 =.02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 =.03; ROHs >3 Mb). Atotal of 43 of 49 nominally significant genescommonfor both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs >1Mb in cases vs 12.11 in controls; 2.986Mb average size of ROHs >2Mb in cases vs 2.889Mb in controls; and 22{\%}of cases with ROHs >3Mb vs 19{\%} of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2 =.006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 =.01; ROHs >1 Mb), encoding a protein from the Claudin family, members of whichwere previously suggested as ADbiomarkers. CONCLUSIONS AND RELEVANCE: To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals.",
author = "Mahdi Ghani and Christiane Reitz and Rong Cheng and Vardarajan, {Badri Narayan} and Gyungah Jun and Christine Sato and Adam Naj and Ruchita Rajbhandary and Wang, {Li San} and Otto Valladares and Lin, {Chiao Feng} and Larson, {Eric B.} and Graff-Radford, {Neill R.} and Denis Evans and {De Jager}, {Philip L.} and Crane, {Paul K.} and Buxbaum, {Joseph D.} and Murrell, {Jill R.} and Towfique Raj and Nilufer Ertekin-Taner and Mark Logue and Baldwin, {Clinton T.} and Green, {Robert C.} and Barnes, {Lisa L.} and Cantwell, {Laura B.} and Fallin, {M. Daniele} and Go, {Rodney C.P.} and Griffith, {Patrick A.} and Obisesan, {Thomas O.} and Manly, {Jennifer J.} and Lunetta, {Kathryn L.} and Kamboh, {M. Ilyas} and Lopez, {Oscar L.} and Bennett, {David A.} and Hugh Hendrie and Hall, {Kathleen S.} and Goate, {Alison M.} and Byrd, {Goldie S.} and Kukull, {Walter A.} and Foroud, {Tatiana M.} and Haines, {Jonathan L.} and Farrer, {Lindsay A.} and Pericak-Vance, {Margaret A.} and Lee, {Joseph H.} and Schellenberg, {Gerard D.} and {St. George-Hyslop}, Peter and Richard Mayeux and Ekaterina Rogaeva and Albert, {Marilyn S.} and Albin, {Roger L.} and Apostolova, {Liana G.} and Arnold, {Steven E.} and Barber, {Robert Clinton} and Barmada, {Michael M.} and Beach, {Thomas G.} and Beecham, {Gary W.} and Duane Beekly and Bigio, {Eileen H.} and Bird, {Thomas D.} and Deborah Blacker and Boeve, {Bradley F.} and Bowen, {James D.} and Adam Boxer and Burke, {James R.} and Guiqing Cai and Cairns, {Nigel J.} and Chuanhai Cao and Carlson, {Chris S.} and Carney, {Regina M.} and Carroll, {Steven L.} and Chui, {Helena C.} and Clark, {David G.} and Cribbs, {David H.} and Crocco, {Elizabeth A.} and Carlos Cruchaga and Charles DeCarli and DeKosky, {Steven T.} and Demirci, {F. Yesim} and Malcolm Dick and Faber, {Kelley M.} and Fallon, {Kenneth B.} and Steven Ferris and Frosch, {Matthew P.} and Galasko, {Douglas R.} and Mary Ganguli and Marla Gearing and Geschwind, {Daniel H.} and Bernardino Ghetti and Gilbert, {John R.} and Sid Gilman and Glass, {Jonathan D.} and Growdon, {John H.} and Hakon Hakonarson and Hamilton, {Ronald L.} and Hamilton-Nelson, {Kara L.} and Vahram Haroutunian and Harrell, {Lindy E.} and Honig, {Lawrence S.} and Hulette, {Christine M.} and Hyman, {Bradley T.} and Jarvik, {Gail P.} and Jicha, {Gregory A.} and Jin, {Lee Way} and Anna Karydas and Kauwe, {John S.K.} and Kaye, {Jeffrey A.} and Ronald Kim and Koo, {Edward H.} and Kowall, {Neil W.} and Kramer, {Joel H.} and Patricia Kramer and LaFerla, {Frank M.} and Lah, {James J.} and Rosalyn Lang-Walker and Leverenz, {James B.} and Levey, {Allan I.} and Ge Li and Lieberman, {Andrew P.} and Lyketsos, {Constantine G.} and Mack, {Wendy J.} and Marson, {Daniel C.} and Frank Martiniuk and Mash, {Deborah C.} and Eliezer Masliah and McCormick, {Wayne C.} and McCurry, {Susan M.} and McDavid, {Andrew N.} and McKee, {Ann C.} and Marsel Mesulam and Miller, {Bruce L.} and Miller, {Carol A.} and Miller, {Joshua W.} and Montine, {Thomas J.} and Morris, {John C.} and Olichney, {John M.} and Parisi, {Joseph E.} and Elaine Peskind and Petersen, {Ronald C.} and Aimee Pierce and Poon, {Wayne W.} and Huntington Potter and Quinn, {Joseph F.} and Ashok Raj and Murray Raskind and Reiman, {Eric M.} and Barry Reisberg and Ringman, {John M.} and Roberson, {Erik D.} and Mary Sano and Saykin, {Andrew J.} and Schneider, {Julie A.} and Schneider, {Lon S.} and Seeley, {William W.} and Smith, {Amanda G.} and Sonnen, {Joshua A.} and Salvatore Spina and Stern, {Robert A.} and Tanzi, {Rudolph E.} and Trojanowski, {John Q.} and Troncoso, {Juan C.} and Tsuang, {Debby W.} and {Van Deerlin}, {Vivianna M.} and {Van Eldik}, {Linda J.} and Vinters, {Harry V.} and Vonsattel, {Jean Paul} and Sandra Weintraub and Welsh-Bohmer, {Kathleen A.} and Jennifer Williamson and Woltjer, {Randall L.} and Wright, {Clinton B.} and Younkin, {Steven G.} and Yu, {Chang En} and Lei Yu",
year = "2015",
month = "11",
day = "1",
doi = "10.1001/jamaneurol.2015.1700",
language = "English",
volume = "72",
pages = "1313--1323",
journal = "JAMA Neurology",
issn = "2168-6149",
publisher = "American Medical Association",
number = "11",

}

Ghani, M, Reitz, C, Cheng, R, Vardarajan, BN, Jun, G, Sato, C, Naj, A, Rajbhandary, R, Wang, LS, Valladares, O, Lin, CF, Larson, EB, Graff-Radford, NR, Evans, D, De Jager, PL, Crane, PK, Buxbaum, JD, Murrell, JR, Raj, T, Ertekin-Taner, N, Logue, M, Baldwin, CT, Green, RC, Barnes, LL, Cantwell, LB, Fallin, MD, Go, RCP, Griffith, PA, Obisesan, TO, Manly, JJ, Lunetta, KL, Kamboh, MI, Lopez, OL, Bennett, DA, Hendrie, H, Hall, KS, Goate, AM, Byrd, GS, Kukull, WA, Foroud, TM, Haines, JL, Farrer, LA, Pericak-Vance, MA, Lee, JH, Schellenberg, GD, St. George-Hyslop, P, Mayeux, R, Rogaeva, E, Albert, MS, Albin, RL, Apostolova, LG, Arnold, SE, Barber, RC, Barmada, MM, Beach, TG, Beecham, GW, Beekly, D, Bigio, EH, Bird, TD, Blacker, D, Boeve, BF, Bowen, JD, Boxer, A, Burke, JR, Cai, G, Cairns, NJ, Cao, C, Carlson, CS, Carney, RM, Carroll, SL, Chui, HC, Clark, DG, Cribbs, DH, Crocco, EA, Cruchaga, C, DeCarli, C, DeKosky, ST, Demirci, FY, Dick, M, Faber, KM, Fallon, KB, Ferris, S, Frosch, MP, Galasko, DR, Ganguli, M, Gearing, M, Geschwind, DH, Ghetti, B, Gilbert, JR, Gilman, S, Glass, JD, Growdon, JH, Hakonarson, H, Hamilton, RL, Hamilton-Nelson, KL, Haroutunian, V, Harrell, LE, Honig, LS, Hulette, CM, Hyman, BT, Jarvik, GP, Jicha, GA, Jin, LW, Karydas, A, Kauwe, JSK, Kaye, JA, Kim, R, Koo, EH, Kowall, NW, Kramer, JH, Kramer, P, LaFerla, FM, Lah, JJ, Lang-Walker, R, Leverenz, JB, Levey, AI, Li, G, Lieberman, AP, Lyketsos, CG, Mack, WJ, Marson, DC, Martiniuk, F, Mash, DC, Masliah, E, McCormick, WC, McCurry, SM, McDavid, AN, McKee, AC, Mesulam, M, Miller, BL, Miller, CA, Miller, JW, Montine, TJ, Morris, JC, Olichney, JM, Parisi, JE, Peskind, E, Petersen, RC, Pierce, A, Poon, WW, Potter, H, Quinn, JF, Raj, A, Raskind, M, Reiman, EM, Reisberg, B, Ringman, JM, Roberson, ED, Sano, M, Saykin, AJ, Schneider, JA, Schneider, LS, Seeley, WW, Smith, AG, Sonnen, JA, Spina, S, Stern, RA, Tanzi, RE, Trojanowski, JQ, Troncoso, JC, Tsuang, DW, Van Deerlin, VM, Van Eldik, LJ, Vinters, HV, Vonsattel, JP, Weintraub, S, Welsh-Bohmer, KA, Williamson, J, Woltjer, RL, Wright, CB, Younkin, SG, Yu, CE & Yu, L 2015, 'Association of long runs of homozygosity with Alzheimer disease among African American individuals', JAMA Neurology, vol. 72, no. 11, pp. 1313-1323. https://doi.org/10.1001/jamaneurol.2015.1700

Association of long runs of homozygosity with Alzheimer disease among African American individuals. / Ghani, Mahdi; Reitz, Christiane; Cheng, Rong; Vardarajan, Badri Narayan; Jun, Gyungah; Sato, Christine; Naj, Adam; Rajbhandary, Ruchita; Wang, Li San; Valladares, Otto; Lin, Chiao Feng; Larson, Eric B.; Graff-Radford, Neill R.; Evans, Denis; De Jager, Philip L.; Crane, Paul K.; Buxbaum, Joseph D.; Murrell, Jill R.; Raj, Towfique; Ertekin-Taner, Nilufer; Logue, Mark; Baldwin, Clinton T.; Green, Robert C.; Barnes, Lisa L.; Cantwell, Laura B.; Fallin, M. Daniele; Go, Rodney C.P.; Griffith, Patrick A.; Obisesan, Thomas O.; Manly, Jennifer J.; Lunetta, Kathryn L.; Kamboh, M. Ilyas; Lopez, Oscar L.; Bennett, David A.; Hendrie, Hugh; Hall, Kathleen S.; Goate, Alison M.; Byrd, Goldie S.; Kukull, Walter A.; Foroud, Tatiana M.; Haines, Jonathan L.; Farrer, Lindsay A.; Pericak-Vance, Margaret A.; Lee, Joseph H.; Schellenberg, Gerard D.; St. George-Hyslop, Peter; Mayeux, Richard; Rogaeva, Ekaterina; Albert, Marilyn S.; Albin, Roger L.; Apostolova, Liana G.; Arnold, Steven E.; Barber, Robert Clinton; Barmada, Michael M.; Beach, Thomas G.; Beecham, Gary W.; Beekly, Duane; Bigio, Eileen H.; Bird, Thomas D.; Blacker, Deborah; Boeve, Bradley F.; Bowen, James D.; Boxer, Adam; Burke, James R.; Cai, Guiqing; Cairns, Nigel J.; Cao, Chuanhai; Carlson, Chris S.; Carney, Regina M.; Carroll, Steven L.; Chui, Helena C.; Clark, David G.; Cribbs, David H.; Crocco, Elizabeth A.; Cruchaga, Carlos; DeCarli, Charles; DeKosky, Steven T.; Demirci, F. Yesim; Dick, Malcolm; Faber, Kelley M.; Fallon, Kenneth B.; Ferris, Steven; Frosch, Matthew P.; Galasko, Douglas R.; Ganguli, Mary; Gearing, Marla; Geschwind, Daniel H.; Ghetti, Bernardino; Gilbert, John R.; Gilman, Sid; Glass, Jonathan D.; Growdon, John H.; Hakonarson, Hakon; Hamilton, Ronald L.; Hamilton-Nelson, Kara L.; Haroutunian, Vahram; Harrell, Lindy E.; Honig, Lawrence S.; Hulette, Christine M.; Hyman, Bradley T.; Jarvik, Gail P.; Jicha, Gregory A.; Jin, Lee Way; Karydas, Anna; Kauwe, John S.K.; Kaye, Jeffrey A.; Kim, Ronald; Koo, Edward H.; Kowall, Neil W.; Kramer, Joel H.; Kramer, Patricia; LaFerla, Frank M.; Lah, James J.; Lang-Walker, Rosalyn; Leverenz, James B.; Levey, Allan I.; Li, Ge; Lieberman, Andrew P.; Lyketsos, Constantine G.; Mack, Wendy J.; Marson, Daniel C.; Martiniuk, Frank; Mash, Deborah C.; Masliah, Eliezer; McCormick, Wayne C.; McCurry, Susan M.; McDavid, Andrew N.; McKee, Ann C.; Mesulam, Marsel; Miller, Bruce L.; Miller, Carol A.; Miller, Joshua W.; Montine, Thomas J.; Morris, John C.; Olichney, John M.; Parisi, Joseph E.; Peskind, Elaine; Petersen, Ronald C.; Pierce, Aimee; Poon, Wayne W.; Potter, Huntington; Quinn, Joseph F.; Raj, Ashok; Raskind, Murray; Reiman, Eric M.; Reisberg, Barry; Ringman, John M.; Roberson, Erik D.; Sano, Mary; Saykin, Andrew J.; Schneider, Julie A.; Schneider, Lon S.; Seeley, William W.; Smith, Amanda G.; Sonnen, Joshua A.; Spina, Salvatore; Stern, Robert A.; Tanzi, Rudolph E.; Trojanowski, John Q.; Troncoso, Juan C.; Tsuang, Debby W.; Van Deerlin, Vivianna M.; Van Eldik, Linda J.; Vinters, Harry V.; Vonsattel, Jean Paul; Weintraub, Sandra; Welsh-Bohmer, Kathleen A.; Williamson, Jennifer; Woltjer, Randall L.; Wright, Clinton B.; Younkin, Steven G.; Yu, Chang En; Yu, Lei.

In: JAMA Neurology, Vol. 72, No. 11, 01.11.2015, p. 1313-1323.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Association of long runs of homozygosity with Alzheimer disease among African American individuals

AU - Ghani, Mahdi

AU - Reitz, Christiane

AU - Cheng, Rong

AU - Vardarajan, Badri Narayan

AU - Jun, Gyungah

AU - Sato, Christine

AU - Naj, Adam

AU - Rajbhandary, Ruchita

AU - Wang, Li San

AU - Valladares, Otto

AU - Lin, Chiao Feng

AU - Larson, Eric B.

AU - Graff-Radford, Neill R.

AU - Evans, Denis

AU - De Jager, Philip L.

AU - Crane, Paul K.

AU - Buxbaum, Joseph D.

AU - Murrell, Jill R.

AU - Raj, Towfique

AU - Ertekin-Taner, Nilufer

AU - Logue, Mark

AU - Baldwin, Clinton T.

AU - Green, Robert C.

AU - Barnes, Lisa L.

AU - Cantwell, Laura B.

AU - Fallin, M. Daniele

AU - Go, Rodney C.P.

AU - Griffith, Patrick A.

AU - Obisesan, Thomas O.

AU - Manly, Jennifer J.

AU - Lunetta, Kathryn L.

AU - Kamboh, M. Ilyas

AU - Lopez, Oscar L.

AU - Bennett, David A.

AU - Hendrie, Hugh

AU - Hall, Kathleen S.

AU - Goate, Alison M.

AU - Byrd, Goldie S.

AU - Kukull, Walter A.

AU - Foroud, Tatiana M.

AU - Haines, Jonathan L.

AU - Farrer, Lindsay A.

AU - Pericak-Vance, Margaret A.

AU - Lee, Joseph H.

AU - Schellenberg, Gerard D.

AU - St. George-Hyslop, Peter

AU - Mayeux, Richard

AU - Rogaeva, Ekaterina

AU - Albert, Marilyn S.

AU - Albin, Roger L.

AU - Apostolova, Liana G.

AU - Arnold, Steven E.

AU - Barber, Robert Clinton

AU - Barmada, Michael M.

AU - Beach, Thomas G.

AU - Beecham, Gary W.

AU - Beekly, Duane

AU - Bigio, Eileen H.

AU - Bird, Thomas D.

AU - Blacker, Deborah

AU - Boeve, Bradley F.

AU - Bowen, James D.

AU - Boxer, Adam

AU - Burke, James R.

AU - Cai, Guiqing

AU - Cairns, Nigel J.

AU - Cao, Chuanhai

AU - Carlson, Chris S.

AU - Carney, Regina M.

AU - Carroll, Steven L.

AU - Chui, Helena C.

AU - Clark, David G.

AU - Cribbs, David H.

AU - Crocco, Elizabeth A.

AU - Cruchaga, Carlos

AU - DeCarli, Charles

AU - DeKosky, Steven T.

AU - Demirci, F. Yesim

AU - Dick, Malcolm

AU - Faber, Kelley M.

AU - Fallon, Kenneth B.

AU - Ferris, Steven

AU - Frosch, Matthew P.

AU - Galasko, Douglas R.

AU - Ganguli, Mary

AU - Gearing, Marla

AU - Geschwind, Daniel H.

AU - Ghetti, Bernardino

AU - Gilbert, John R.

AU - Gilman, Sid

AU - Glass, Jonathan D.

AU - Growdon, John H.

AU - Hakonarson, Hakon

AU - Hamilton, Ronald L.

AU - Hamilton-Nelson, Kara L.

AU - Haroutunian, Vahram

AU - Harrell, Lindy E.

AU - Honig, Lawrence S.

AU - Hulette, Christine M.

AU - Hyman, Bradley T.

AU - Jarvik, Gail P.

AU - Jicha, Gregory A.

AU - Jin, Lee Way

AU - Karydas, Anna

AU - Kauwe, John S.K.

AU - Kaye, Jeffrey A.

AU - Kim, Ronald

AU - Koo, Edward H.

AU - Kowall, Neil W.

AU - Kramer, Joel H.

AU - Kramer, Patricia

AU - LaFerla, Frank M.

AU - Lah, James J.

AU - Lang-Walker, Rosalyn

AU - Leverenz, James B.

AU - Levey, Allan I.

AU - Li, Ge

AU - Lieberman, Andrew P.

AU - Lyketsos, Constantine G.

AU - Mack, Wendy J.

AU - Marson, Daniel C.

AU - Martiniuk, Frank

AU - Mash, Deborah C.

AU - Masliah, Eliezer

AU - McCormick, Wayne C.

AU - McCurry, Susan M.

AU - McDavid, Andrew N.

AU - McKee, Ann C.

AU - Mesulam, Marsel

AU - Miller, Bruce L.

AU - Miller, Carol A.

AU - Miller, Joshua W.

AU - Montine, Thomas J.

AU - Morris, John C.

AU - Olichney, John M.

AU - Parisi, Joseph E.

AU - Peskind, Elaine

AU - Petersen, Ronald C.

AU - Pierce, Aimee

AU - Poon, Wayne W.

AU - Potter, Huntington

AU - Quinn, Joseph F.

AU - Raj, Ashok

AU - Raskind, Murray

AU - Reiman, Eric M.

AU - Reisberg, Barry

AU - Ringman, John M.

AU - Roberson, Erik D.

AU - Sano, Mary

AU - Saykin, Andrew J.

AU - Schneider, Julie A.

AU - Schneider, Lon S.

AU - Seeley, William W.

AU - Smith, Amanda G.

AU - Sonnen, Joshua A.

AU - Spina, Salvatore

AU - Stern, Robert A.

AU - Tanzi, Rudolph E.

AU - Trojanowski, John Q.

AU - Troncoso, Juan C.

AU - Tsuang, Debby W.

AU - Van Deerlin, Vivianna M.

AU - Van Eldik, Linda J.

AU - Vinters, Harry V.

AU - Vonsattel, Jean Paul

AU - Weintraub, Sandra

AU - Welsh-Bohmer, Kathleen A.

AU - Williamson, Jennifer

AU - Woltjer, Randall L.

AU - Wright, Clinton B.

AU - Younkin, Steven G.

AU - Yu, Chang En

AU - Yu, Lei

PY - 2015/11/1

Y1 - 2015/11/1

N2 - IMPORTANCE: Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3%of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays. OBJECTIVE: To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals. DESIGN, SETTING, AND PARTICIPANTS: Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-basedROHmeasurementswere analyzed using rawor imputed genotype data.We studied the rawgenotypes from 2 case-control subsets grouped based on SNP array: Alzheimer's Disease Genetics Consortium data set (871 cases and 1620control individuals) and Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals).We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals. MAIN OUTCOMES AND MEASURES: The ROHs larger than 1Mb, 2Mb, or 3Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses. RESULTS: The African American cohort had a lowdegree of inbreeding (F × 0.006). In the Alzheimer's Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2Mb (P =.004) or greater than 3Mb (P =.02), aswell as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 =.04; ROHs >2 Mb). In the Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 =.02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 =.03; ROHs >3 Mb). Atotal of 43 of 49 nominally significant genescommonfor both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs >1Mb in cases vs 12.11 in controls; 2.986Mb average size of ROHs >2Mb in cases vs 2.889Mb in controls; and 22%of cases with ROHs >3Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2 =.006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 =.01; ROHs >1 Mb), encoding a protein from the Claudin family, members of whichwere previously suggested as ADbiomarkers. CONCLUSIONS AND RELEVANCE: To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals.

AB - IMPORTANCE: Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3%of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays. OBJECTIVE: To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals. DESIGN, SETTING, AND PARTICIPANTS: Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-basedROHmeasurementswere analyzed using rawor imputed genotype data.We studied the rawgenotypes from 2 case-control subsets grouped based on SNP array: Alzheimer's Disease Genetics Consortium data set (871 cases and 1620control individuals) and Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals).We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals. MAIN OUTCOMES AND MEASURES: The ROHs larger than 1Mb, 2Mb, or 3Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses. RESULTS: The African American cohort had a lowdegree of inbreeding (F × 0.006). In the Alzheimer's Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2Mb (P =.004) or greater than 3Mb (P =.02), aswell as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 =.04; ROHs >2 Mb). In the Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 =.02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 =.03; ROHs >3 Mb). Atotal of 43 of 49 nominally significant genescommonfor both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs >1Mb in cases vs 12.11 in controls; 2.986Mb average size of ROHs >2Mb in cases vs 2.889Mb in controls; and 22%of cases with ROHs >3Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2 =.006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 =.01; ROHs >1 Mb), encoding a protein from the Claudin family, members of whichwere previously suggested as ADbiomarkers. CONCLUSIONS AND RELEVANCE: To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals.

UR - http://www.scopus.com/inward/record.url?scp=84946752797&partnerID=8YFLogxK

U2 - 10.1001/jamaneurol.2015.1700

DO - 10.1001/jamaneurol.2015.1700

M3 - Article

VL - 72

SP - 1313

EP - 1323

JO - JAMA Neurology

JF - JAMA Neurology

SN - 2168-6149

IS - 11

ER -