TY - JOUR
T1 - Linkage analyses in Caribbean Hispanic families identify novel loci associated with familial late-onset Alzheimer's disease
AU - Barral, Sandra
AU - Cheng, Rong
AU - Reitz, Christiane
AU - Vardarajan, Badri
AU - Lee, Joseph
AU - Kunkle, Brian
AU - Beecham, Gary
AU - Cantwell, Laura S.
AU - Pericak-Vance, Margaret A.
AU - Farrer, Lindsay A.
AU - Haines, Jonathan L.
AU - Goate, Alison M.
AU - Foroud, Tatiana
AU - Boerwinkle, Eric
AU - Schellenberg, Gerard D.
AU - Mayeux, Richard
N1 - Funding Information:
This work was supported by National Institutes of Health/National Institute on Aging grants R37AG015473 , UO1AG032984 , and 5P50AG008702-25 . C.R. was further supported by a Paul B. Beeson Career Development Award K23AG034550. L.A.F. was supported by National Institutes of Health grants R01-AG025259 and P30-AG13846 . The funding sources had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the article; and decision to submit the article for publication.
Publisher Copyright:
© 2015 The Alzheimer's Association.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - Introduction We performed linkage analyses in Caribbean Hispanic families with multiple late-onset Alzheimer's disease (LOAD) cases to identify regions that may contain disease causative variants. Methods We selected 67 LOAD families to perform genome-wide linkage scan. Analysis of the linked regions was repeated using the entire sample of 282 families. Validated chromosomal regions were analyzed using joint linkage and association. Results We identified 26 regions linked to LOAD (HLOD ≥3.6). We validated 13 of the regions (HLOD ≥2.5) using the entire family sample. The strongest signal was at 11q12.3 (rs2232932: HLODmax = 4.7, Pjoint = 6.6 × 10-6), a locus located ∼2 Mb upstream of the membrane-spanning 4A gene cluster. We additionally identified a locus at 7p14.3 (rs10255835: HLODmax = 4.9, Pjoint = 1.2 × 10-5), a region harboring genes associated with the nervous system (GARS, GHRHR, and NEUROD6). Discussion Future sequencing efforts should focus on these regions because they may harbor familial LOAD causative mutations.
AB - Introduction We performed linkage analyses in Caribbean Hispanic families with multiple late-onset Alzheimer's disease (LOAD) cases to identify regions that may contain disease causative variants. Methods We selected 67 LOAD families to perform genome-wide linkage scan. Analysis of the linked regions was repeated using the entire sample of 282 families. Validated chromosomal regions were analyzed using joint linkage and association. Results We identified 26 regions linked to LOAD (HLOD ≥3.6). We validated 13 of the regions (HLOD ≥2.5) using the entire family sample. The strongest signal was at 11q12.3 (rs2232932: HLODmax = 4.7, Pjoint = 6.6 × 10-6), a locus located ∼2 Mb upstream of the membrane-spanning 4A gene cluster. We additionally identified a locus at 7p14.3 (rs10255835: HLODmax = 4.9, Pjoint = 1.2 × 10-5), a region harboring genes associated with the nervous system (GARS, GHRHR, and NEUROD6). Discussion Future sequencing efforts should focus on these regions because they may harbor familial LOAD causative mutations.
KW - Caribbean Hispanic families
KW - Joint linkage and association
KW - Late-onset Alzheimer's disease
KW - Linkage analysis
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U2 - 10.1016/j.jalz.2015.07.487
DO - 10.1016/j.jalz.2015.07.487
M3 - Article
C2 - 26433351
AN - SCOPUS:84952630466
VL - 11
SP - 1397
EP - 1406
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
SN - 1552-5260
IS - 12
ER -