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TOMM40 Poly-T Length Variant and Age-At-Onset in Familial AD Caused by PSEN1 and PSEN2 Mutation
Poster Presentations P1 overexpressed in LCL from DS individuals. SYNJ1 gene codes for the phosphoinositide phosphatase synaptojanin 1 protein, a key regulator of the signalling phospholipids phosphatidylinositol-4,5-biphosphate [PtdIns (4,5) P2]. PtdIns (4,5)P2 has been shown to interact with clathrin coated pits and to regulate endocytosis. Finally, we demonstrate that synaptojanin 1 overexpression by itself, in neuroblastoma cells and TgSYNJ1 mice, leads to the enlargement of early endosomes. P1-244
A GENOME-WIDE STUDY OF FAMILIAL ALZHEIMER’S DISEASE SUPPORTS ADDITIONAL CANDIDATE GENES: THE NIA-LOAD/NCRAD FAMILY STUDY
Joseph Lee1, Rong Cheng1, Nathan Pankratz2, Ellen Wijsman3, Thomas Bird3, Tatiana Foroud2, Richard Mayeux1 NIA-LOAD/NCRAD Family Study Group11Columbia University, New York, New York, United States; 2Indiana University, Indianapolis, Indiana, United States; 3 University of Washington, Seattle, Washington, United States. Background: Many candidate genes for Alzheimer’s disease (AD) have been reported from multiple genome-wide association studies using thousands of clinical AD cases and controls. These signals are being examined now to separate true positives from false positives and to identify putative variants. Here we present the results from our genome-wide linkage analysis for a familial form of AD. Methods: We examined a large collection of Caucasian families (n ¼ 620) with at least two persons affected with late onset Alzheimer Disease (LOAD). We then restricted the analysis to families with four or more persons affected with LOAD to see whether there exist additional candidate genes that are unique to families with highly familial (¼4 affecteds) AD. The details of the study design are discussed elsewhere (Wijsman, 2011). We genotyped all samples (n ¼ 2477) using the Illumina 610 Duo. Results: In the first stage, we identified candidate loci on 2q31.1, 3p24.3, 3q13.12, 4q13.3, 6p22.3, 7p22.2, 8q11.23, 9p21.3, 10p14, 11q22.1, 12q24.32, 14q32.33, 19q13.32 that had nonparametric LOD scores exceeding three. As previous studies have shown, rs2075650 at 19q13.32 flanking APOE had the strongest LOD score in the current study. We then examined a subset of families with four or more affected persons (n ¼ 243 families, 1217 genotyped members), and found that six loci had LOD scores exceeding four, specifically at 6p22.3, 8q11.23, 11q22.1, 11q24.2, 18q21.1, and 19p13.12. Signals at 6p22.3, 11q22.1, 11q24.2, and 19p13.12 were unique to families with ¼4 affecteds, while the other two loci were significantly supported in all families. Five loci had the following candidate genes: FLJ22536 (6p22.3), CNTN5 (11q22.1), KIRREL3 (11q24.2), MYO5B (18q21.1) and CASP14 (19p13.12). Conclusions: Here we present new candidate genes that are likely to be associated with familial AD in a Caucasian cohort. P1-245
TOMM40 POLY-T LENGTH VARIANT AND AGE-AT-ONSET IN FAMILIAL AD CAUSED BY PSEN1 AND PSEN2 MUTATION
Gail (Ge) Li1, Lynn Bekris2, Ellen Steinbart2, Thomas Bird2, Chang-en Yu2, 1University of Washington, Seattle, Washington, United States; 2VA Puget Sound Health Care System and University of Washington, Seattle, Washington, United States. Background: Our previous study showed that familial Alzheimer’s disease (AD) caused by apresenilin 2 (PSEN2) mutation (N141I) has similar neuropathology but a wide variation in age-at-onset. A recent study found that the length of a poly-T nucleotide repeat (rs10524523) within intron 6 of the translocase of outer mitochondrial membrane 40 homolog (TOMM40) gene, which is adjacent to apolipoprotein E (APOE), is associated with age-at-onset in late-onset AD. In this study, we examine associations between TOMM40 poly-T length and age-at-onset in AD patients carrying either presenilin 1 (PSEN1 on chromosome 14) or PSEN2 mutations. Methods: Thirty-two PSEN1 mutation carriers and 27 PSEN2 mutation carriers with AD and APOE e3/e3 genotype were recruited from the University of Washington ADRC. AD diagnosis and age-at-onset were determined based on history and clinical evaluation.
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The rs10524523 poly-T length was genotyped using a short tandem repeats genotyping assay developed in Dr. Yu’s laboratory. Poly-T length was dichotomized into the short (< 20) and long (¼ 20). The age-at-onset was compared between those with and without long poly-T variants. To account for this intra-family correlation of age-at-onset, standard error was estimated using robust linear regression. Results: In AD patients with PSEN2 mutations, the age-at-onset was an average of 7 years earlier for patients with long poly-T variants than patients with short/short variants (p ¼ 0.036). After accounting for the intra-family correlation, the significance of the difference dropped slightly to p ¼ 0.06. In patients with PSEN1 mutations, age-at-onset did not differ by presence of long poly-T variants (Table 1, p ¼ 0.82). Conclusions: PSEN2 carriers with at least one copy of the long poly-T have on average an AD age-at-onset 7 years earlier than those without the long poly-T. This finding is consistent with previous report in late-onset AD. Further study is needed to determine whether the lack of association between TOMM40 poly-T and age-at-onset in persons with PSEN1 mutation is due to heterogeneity of PSEN1 mutations or a different mechanism of TOMM40 in AD. P1-246
GENOME-WIDE ASSOCIATION ANALYSIS IDENTIFIES NOVEL LOCI ASSOCIATED WITH THE ONSET AGE AMONG CASES WITH LATE-ONSET ALZHEIMER’S DISEASE
Eden Martin1, Adam Naj1, Yo S. Park1, Paul Gallins1, Kara Hamilton1, Ruchita Rajbhandary1, Jonathan Haines2, Margaret Pericak-Vance1 The Alzheimer’s Disease Genetics Consortium31University of Miami Miller School of Medicine, Miami, Florida, United States; 2Vanderbilt University Medical Center, Nashville, Tennessee, United States; 3University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States. Background: While studies of late-onset Alzheimer Disease (LOAD) have found multiple loci (APOE, CLU, PICALM, CR1, and BIN1) contributing to risk, genetic contributors to onset age of LOAD have not been widely studied, with variation at only a few loci (e.g., APOE, GSTO1) known to contribute. We examined the association of genomic variation with age-at-onset (AAO) in 9,160 LOAD cases from the Alzheimer’s Disease Genetics Consortium (ADGC). Methods: We examined association with AAO for 2,324,889 genotyped and imputed SNPs among 9,160 LOAD cases from 14 datasets of the ADGC. AAO was modeled linearly using generalized estimating equations (GEE) with adjustment for population substructure and cohort effects. Extended models adjusted for sex and dosage of the APOE e4 allele (0, 1, or 2 copies) as covariates. We also examined the AAO effect by comparing differences in genotype frequency between the youngest (lowest quartile, N ¼ 2,450) and oldest (highest quartile, N ¼ 2,757) cases using GEE with a logistic model. Results: Primary AAO analyses using all 9,160 cases confirmed association 100 ~ of APOE region variation with AAO (APOC1, P ¼ 4.72A—10 ). After adjustment for sex and dosage of the APOE e4 allele, with which associations in APOE faded as expected, the AD candidate gene VDR demonstrated association with AAO near genome-wide significance (P ¼ 7 ~ 6.18A—10 ), as did several other regions: the 8q24.11 region including 6 6 ~ ~ ; 6q16.1, P ¼ 6.17A—10 ; CIB4, P ¼ RAD21, P ¼ 2.38A—10 6 6 ~ ~ 7.70A—10 ; ABCC4, P ¼ 9.25A—10 . Dichotomized analyses of youngest/oldest case quartiles demonstrated differences in AAO associa69 ~ tion among loci near APOE (e.g., APOC1, P ¼ 3.17A—10 ), with more modest associations (P < 105) at other loci (MPP2/MPP3/BCAM/ 7 ~ ~ DBF4B in 17q21.31 region, P ¼ 2.67A—10 ; CHGB, P ¼ 5.54A— 6 ~ 106; 10p12.33, P ¼ 6.61A—10 ). Adjusting for sex and APOE e4 dos7 ~ ; age, notable signals included chromosome 17p12, P ¼ 6.42A—10 7 6 ~ ~ MGC34034, P ¼ 6.51A—10 ; OR8A1, P ¼ 1.08A—10 ; RAD21, P ¼ 6 6 ~ ~ 3.00A—10 ; MPP2/MPP3, P ¼ 4.02A—10 ; 10p12.33 region, P ¼ 6 6 ~ ~ 5.00A—10 ; DCC, P ¼ 8.51A—10 ). Conclusions: In AAO analyses among LOAD cases, we confirmed associations of the variation near 19q13.32 (APOE region) with genome-wide statistical significance and detected strong associations near the AD candidate gene VDR, after adjustment for sex and APOE e4 dosage. Another locus with associations in
A GENOME-WIDE STUDY OF FAMILIAL ALZHEIMER’S DISEASE SUPPORTS ADDITIONAL CANDIDATE GENES: THE NIA-LOAD/NCRAD FAMILY STUDY
Joseph Lee1, Rong Cheng1, Nathan Pankratz2, Ellen Wijsman3, Thomas Bird3, Tatiana Foroud2, Richard Mayeux1 NIA-LOAD/NCRAD Family Study Group11Columbia University, New York, New York, United States; 2Indiana University, Indianapolis, Indiana, United States; 3 University of Washington, Seattle, Washington, United States. Background: Many candidate genes for Alzheimer’s disease (AD) have been reported from multiple genome-wide association studies using thousands of clinical AD cases and controls. These signals are being examined now to separate true positives from false positives and to identify putative variants. Here we present the results from our genome-wide linkage analysis for a familial form of AD. Methods: We examined a large collection of Caucasian families (n ¼ 620) with at least two persons affected with late onset Alzheimer Disease (LOAD). We then restricted the analysis to families with four or more persons affected with LOAD to see whether there exist additional candidate genes that are unique to families with highly familial (¼4 affecteds) AD. The details of the study design are discussed elsewhere (Wijsman, 2011). We genotyped all samples (n ¼ 2477) using the Illumina 610 Duo. Results: In the first stage, we identified candidate loci on 2q31.1, 3p24.3, 3q13.12, 4q13.3, 6p22.3, 7p22.2, 8q11.23, 9p21.3, 10p14, 11q22.1, 12q24.32, 14q32.33, 19q13.32 that had nonparametric LOD scores exceeding three. As previous studies have shown, rs2075650 at 19q13.32 flanking APOE had the strongest LOD score in the current study. We then examined a subset of families with four or more affected persons (n ¼ 243 families, 1217 genotyped members), and found that six loci had LOD scores exceeding four, specifically at 6p22.3, 8q11.23, 11q22.1, 11q24.2, 18q21.1, and 19p13.12. Signals at 6p22.3, 11q22.1, 11q24.2, and 19p13.12 were unique to families with ¼4 affecteds, while the other two loci were significantly supported in all families. Five loci had the following candidate genes: FLJ22536 (6p22.3), CNTN5 (11q22.1), KIRREL3 (11q24.2), MYO5B (18q21.1) and CASP14 (19p13.12). Conclusions: Here we present new candidate genes that are likely to be associated with familial AD in a Caucasian cohort. P1-245
TOMM40 POLY-T LENGTH VARIANT AND AGE-AT-ONSET IN FAMILIAL AD CAUSED BY PSEN1 AND PSEN2 MUTATION
Gail (Ge) Li1, Lynn Bekris2, Ellen Steinbart2, Thomas Bird2, Chang-en Yu2, 1University of Washington, Seattle, Washington, United States; 2VA Puget Sound Health Care System and University of Washington, Seattle, Washington, United States. Background: Our previous study showed that familial Alzheimer’s disease (AD) caused by apresenilin 2 (PSEN2) mutation (N141I) has similar neuropathology but a wide variation in age-at-onset. A recent study found that the length of a poly-T nucleotide repeat (rs10524523) within intron 6 of the translocase of outer mitochondrial membrane 40 homolog (TOMM40) gene, which is adjacent to apolipoprotein E (APOE), is associated with age-at-onset in late-onset AD. In this study, we examine associations between TOMM40 poly-T length and age-at-onset in AD patients carrying either presenilin 1 (PSEN1 on chromosome 14) or PSEN2 mutations. Methods: Thirty-two PSEN1 mutation carriers and 27 PSEN2 mutation carriers with AD and APOE e3/e3 genotype were recruited from the University of Washington ADRC. AD diagnosis and age-at-onset were determined based on history and clinical evaluation.
S189
The rs10524523 poly-T length was genotyped using a short tandem repeats genotyping assay developed in Dr. Yu’s laboratory. Poly-T length was dichotomized into the short (< 20) and long (¼ 20). The age-at-onset was compared between those with and without long poly-T variants. To account for this intra-family correlation of age-at-onset, standard error was estimated using robust linear regression. Results: In AD patients with PSEN2 mutations, the age-at-onset was an average of 7 years earlier for patients with long poly-T variants than patients with short/short variants (p ¼ 0.036). After accounting for the intra-family correlation, the significance of the difference dropped slightly to p ¼ 0.06. In patients with PSEN1 mutations, age-at-onset did not differ by presence of long poly-T variants (Table 1, p ¼ 0.82). Conclusions: PSEN2 carriers with at least one copy of the long poly-T have on average an AD age-at-onset 7 years earlier than those without the long poly-T. This finding is consistent with previous report in late-onset AD. Further study is needed to determine whether the lack of association between TOMM40 poly-T and age-at-onset in persons with PSEN1 mutation is due to heterogeneity of PSEN1 mutations or a different mechanism of TOMM40 in AD. P1-246
GENOME-WIDE ASSOCIATION ANALYSIS IDENTIFIES NOVEL LOCI ASSOCIATED WITH THE ONSET AGE AMONG CASES WITH LATE-ONSET ALZHEIMER’S DISEASE
Eden Martin1, Adam Naj1, Yo S. Park1, Paul Gallins1, Kara Hamilton1, Ruchita Rajbhandary1, Jonathan Haines2, Margaret Pericak-Vance1 The Alzheimer’s Disease Genetics Consortium31University of Miami Miller School of Medicine, Miami, Florida, United States; 2Vanderbilt University Medical Center, Nashville, Tennessee, United States; 3University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States. Background: While studies of late-onset Alzheimer Disease (LOAD) have found multiple loci (APOE, CLU, PICALM, CR1, and BIN1) contributing to risk, genetic contributors to onset age of LOAD have not been widely studied, with variation at only a few loci (e.g., APOE, GSTO1) known to contribute. We examined the association of genomic variation with age-at-onset (AAO) in 9,160 LOAD cases from the Alzheimer’s Disease Genetics Consortium (ADGC). Methods: We examined association with AAO for 2,324,889 genotyped and imputed SNPs among 9,160 LOAD cases from 14 datasets of the ADGC. AAO was modeled linearly using generalized estimating equations (GEE) with adjustment for population substructure and cohort effects. Extended models adjusted for sex and dosage of the APOE e4 allele (0, 1, or 2 copies) as covariates. We also examined the AAO effect by comparing differences in genotype frequency between the youngest (lowest quartile, N ¼ 2,450) and oldest (highest quartile, N ¼ 2,757) cases using GEE with a logistic model. Results: Primary AAO analyses using all 9,160 cases confirmed association 100 ~ of APOE region variation with AAO (APOC1, P ¼ 4.72A—10 ). After adjustment for sex and dosage of the APOE e4 allele, with which associations in APOE faded as expected, the AD candidate gene VDR demonstrated association with AAO near genome-wide significance (P ¼ 7 ~ 6.18A—10 ), as did several other regions: the 8q24.11 region including 6 6 ~ ~ ; 6q16.1, P ¼ 6.17A—10 ; CIB4, P ¼ RAD21, P ¼ 2.38A—10 6 6 ~ ~ 7.70A—10 ; ABCC4, P ¼ 9.25A—10 . Dichotomized analyses of youngest/oldest case quartiles demonstrated differences in AAO associa69 ~ tion among loci near APOE (e.g., APOC1, P ¼ 3.17A—10 ), with more modest associations (P < 105) at other loci (MPP2/MPP3/BCAM/ 7 ~ ~ DBF4B in 17q21.31 region, P ¼ 2.67A—10 ; CHGB, P ¼ 5.54A— 6 ~ 106; 10p12.33, P ¼ 6.61A—10 ). Adjusting for sex and APOE e4 dos7 ~ ; age, notable signals included chromosome 17p12, P ¼ 6.42A—10 7 6 ~ ~ MGC34034, P ¼ 6.51A—10 ; OR8A1, P ¼ 1.08A—10 ; RAD21, P ¼ 6 6 ~ ~ 3.00A—10 ; MPP2/MPP3, P ¼ 4.02A—10 ; 10p12.33 region, P ¼ 6 6 ~ ~ 5.00A—10 ; DCC, P ¼ 8.51A—10 ). Conclusions: In AAO analyses among LOAD cases, we confirmed associations of the variation near 19q13.32 (APOE region) with genome-wide statistical significance and detected strong associations near the AD candidate gene VDR, after adjustment for sex and APOE e4 dosage. Another locus with associations in