@article {1450, title = {Surveillance and ascertainment of cardiovascular events. The Cardiovascular Health Study.}, journal = {Ann Epidemiol}, volume = {5}, year = {1995}, month = {1995 Jul}, pages = {278-85}, abstract = {

While previous prospective multicenter studies have conducted cardiovascular disease surveillance, few have detailed the techniques relating to the ascertainment of and data collection for events. The Cardiovascular Health Study (CHS) is a population-based study of coronary heart disease and stroke in older adults. This article summarizes the CHS events protocol and describes the methods of surveillance and ascertainment of hospitalized and nonhospitalized events, the use of medical records and other support documents, organizational issues at the field center level, and the classification of events through an adjudication process. We present data on incidence and mortality, the classification of adjudicated events, and the agreement between classification by the Events Subcommittee and the medical records diagnostic codes. The CHS techniques are a successful model for complete ascertainment, investigation, and documentation of events in an older cohort.

}, keywords = {Aged, Cerebrovascular Disorders, Coronary Disease, Epidemiologic Methods, Female, Hospitalization, Humans, Incidence, Longitudinal Studies, Male, Population Surveillance, Quality Control, United States}, issn = {1047-2797}, author = {Ives, D G and Fitzpatrick, A L and Bild, D E and Psaty, B M and Kuller, L H and Crowley, P M and Cruise, R G and Theroux, S} } @article {1489, title = {Use of calcium channel blockers and breast carcinoma risk in postmenopausal women.}, journal = {Cancer}, volume = {80}, year = {1997}, month = {1997 Oct 15}, pages = {1438-47}, abstract = {

BACKGROUND: The use of calcium channel blockers in an elderly population recently was reported to be associated with the incidence of cancer. The Cardiovascular Health Study, a multisite observational cohort study, provided the opportunity to investigate the epidemiologic association between the use of calcium channel blockers and breast carcinoma risk in 3198 women age > or = 65 years.

METHODS: Standard questionnaires and clinical procedures were administered at four study sites annually from 1989-1990 to 1993-1994. Drug usage was assessed by a medication inventory and hospitalizations for 75 incident invasive breast carcinoma cases were identified using International Classification of Diseases-9 Clinical Modification codes. Time-dependent Cox proportional hazards regression models were used to assess associations between incident breast carcinoma and the use of specific antihypertensive medication including calcium channel blockers.

RESULTS: In adjusted Cox proportional hazards models, an elevated risk of breast carcinoma was associated with use of calcium channel blockers (hazard ratio [HR]: 2.57; 95\% confidence interval [CI], 1.47-4.49). This association persisted when the comparison group was users of other antihypertensive medication. No associations between the use of other antihypertensive medication with incident breast carcinoma were found. Associations were enhanced by assessment of high dose at baseline (HR: 4.42; 95\% CI, 1.37-14.27) and when calcium channel blockers were combined with estrogen use (HR: 4.48; 95\% CI, 1.58-12.75). The association was found to be strongest for the use of estrogens with immediate release calcium channel blockers (HR: 8.48; 95\% CI, 2.99-24.08).

CONCLUSIONS: Although the number of cases was limited in this observational study, associations found between the use of calcium channel blockers and incident invasive breast carcinoma warrant further investigation. Site specific carcinomas should be included as an outcome of ongoing and planned long term clinical trials using calcium channel blockers.

}, keywords = {Age Factors, Aged, Breast Neoplasms, Calcium Channel Blockers, Cohort Studies, Estrogens, Female, Humans, Postmenopause, Proportional Hazards Models, Risk Factors}, issn = {0008-543X}, author = {Fitzpatrick, A L and Daling, J R and Furberg, C D and Kronmal, R A and Weissfeld, J L} } @article {666, title = {Hypertension, heart rate, use of antihypertensives, and incident prostate cancer.}, journal = {Ann Epidemiol}, volume = {11}, year = {2001}, month = {2001 Nov}, pages = {534-42}, abstract = {

PURPOSE: Recent studies have reported conflicting results on a possible relationship between hypertension, heart rate, and prostate cancer. A model has been developed suggesting that high blood pressure and high heart rate may both be markers for increased central sympathetic nervous activity, which may result in androgen-mediated stimulation of prostate cancer growth.

METHODS: In this study we examined the associations between hypertension, heart rate, use of antihypertensive medications, and incident prostate cancer in a cohort of 2442 men. Data from the Cardiovascular Health Study (CHS), an NHLBI-sponsored observational study of adults age 65 or older in four U.S. communities, were analyzed using Cox proportional hazards regression. Seated systolic and diastolic blood pressures were measured using a standardized protocol at the initial clinical examination and annually at follow-up visits. Medications data were transcribed by trained interviewers from prescription medication containers brought into the clinic by participants.

RESULTS: A total of 209 cases of incident prostate cancer were identified from either an ICD-9 code of 185 in hospital medical records (n = 130) or by self-report from annual surveillance interviews (n = 79). An average of 5.6 years of follow-up was available for analyses. No associations between blood pressure measures at entry into the study and prostate cancer were found, although these results may have been affected by subsequent treatment of hypertension. An association between resting heart rate (HR) equal to or greater than 80 beats per minute and incident prostate cancer was found compared to men with a rate of less than 60 beats per minute (HR: 1.6, 95\% confidence interval [CI]: 1.03-2.5). An inverse association was found between risk of incident prostate cancer and use of any antihypertensive medication (HR: 0.7, 95\% CI: 0.5-0.9). A test of heterogeneity found no difference between use of the specific classes of antihypertensive medication and the association with prostate cancer risk.

CONCLUSIONS: These data tend to support the hypothesized causal pathway between vascular disease markers and prostate cancer.

}, keywords = {Aged, Antihypertensive Agents, Cohort Studies, Heart Rate, Humans, Hypertension, Incidence, Male, Proportional Hazards Models, Prostatic Neoplasms, Risk, United States}, issn = {1047-2797}, doi = {10.1016/s1047-2797(01)00246-0}, author = {Fitzpatrick, A L and Daling, J R and Furberg, C D and Kronmal, R A and Weissfeld, J L} } @article {870, title = {Benefits of fatty fish on dementia risk are stronger for those without APOE epsilon4.}, journal = {Neurology}, volume = {65}, year = {2005}, month = {2005 Nov 08}, pages = {1409-14}, abstract = {

OBJECTIVE: To compare associations of lean fish vs fatty fish (tuna or other fish) intake with dementia, Alzheimer disease (AD), and vascular dementia (VaD) and in relation to APOE epsilon4 status in the Cardiovascular Health Cognition Study (CHCS).

METHODS: Fish intake was assessed by food frequency questionnaires. Incident dementia, AD, and VaD were determined through a series of cognitive tests, physician{\textquoteright}s assessment, and committee consensus. We used Cox proportional hazards regression to calculate hazard ratios of dementia, AD, and VaD with lean fried fish, fatty fish, or total fish intake, which were then stratified by the presence of APOE epsilon4.

RESULTS: Although consumption of lean fried fish had no protective effect, consumption of fatty fish more than twice per week was associated with a reduction in risk of dementia by 28\% (95\% CI: 0.51 to 1.02), and AD by 41\% (95\% CI: 0.36 to 0.95) in comparison to those who ate fish less than once per month. Stratification by APOE epsilon4 showed this effect to be selective to those without the epsilon4 allele. Adjustment by education and income attenuated the effect.

CONCLUSION: In the Cardiovascular Health Cognition Study, consumption of fatty fish was associated with a reduced risk of dementia and Alzheimer disease for those without the APOE epsilon4 allele.

}, keywords = {Aged, Alzheimer Disease, Apolipoprotein E4, Apolipoproteins E, Cohort Studies, Dementia, Dietary Fats, Unsaturated, Fatty Acids, Omega-3, Feeding Behavior, Female, Fish Oils, Fish Products, Food, Formulated, Genetic Predisposition to Disease, Humans, Incidence, Male, Risk Factors, Socioeconomic Factors, Surveys and Questionnaires}, issn = {1526-632X}, doi = {10.1212/01.wnl.0000183148.34197.2e}, author = {Huang, T L and Zandi, P P and Tucker, K L and Fitzpatrick, A L and Kuller, L H and Fried, L P and Burke, G L and Carlson, M C} } @article {1031, title = {Knee height and arm span: a reflection of early life environment and risk of dementia.}, journal = {Neurology}, volume = {70}, year = {2008}, month = {2008 May 06}, pages = {1818-26}, abstract = {

OBJECTIVES: To determine if anthropometric measures, as markers of early life environment, are associated with risk of dementia, Alzheimer disease (AD), and vascular dementia (VaD).

METHODS: A total of 2,798 subjects were followed as part of the Cardiovascular Health Cognition Study for an average of 5.4 years; 480 developed dementia. Knee height was measured 3 years prior to and arm span 4 years after the study{\textquoteright}s baseline. Cox proportional hazard models were used to examine their association with subsequent risk of dementia, AD, and VaD.

RESULTS: Among women, greater knee height and arm span were associated with lower risks of dementia (knee height: HR per 1-inch increase 0.84; 95\% CI 0.74-0.96; arm span: HR per 1-inch increase 0.93; 95\% CI 0.88-0.98) and AD (knee height: HR per 1-inch increase 0.78; 95\% CI 0.65-0.93; arm span: HR per 1-inch increase 0.90; 95\% CI 0.85-0.96). Women in the lowest quartile of arm span had approximately 1.5 times greater risk of dementia (HR 1.45; 95\% CI 1.03-2.05) and AD (HR 1.70; 95\% CI 1.10-2.62) than other women. Among men, only arm span was associated with lower risks of dementia (HR per 1-inch increase 0.94; 95\% CI 0.89-1.00) and AD (HR per 1-inch increase 0.92; 95\% CI 0.84-1.00). For each gender, knee height was not associated with VaD, while arm span was associated with a nonsignificant lower risk of VaD.

CONCLUSIONS: Our findings with knee height and arm span are consistent with previous reports and suggest early life environment may play an important role in the determination of future dementia risk.

}, keywords = {Aged, Aged, 80 and over, Aging, Anthropometry, Arm, Body Height, Brain, Child, Child, Preschool, Dementia, Environment, Female, Follow-Up Studies, Humans, Infant, Infant, Newborn, Knee, Male, Middle Aged, Prospective Studies, Risk Factors, Sex Characteristics, Skeleton}, issn = {1526-632X}, doi = {10.1212/01.wnl.0000311444.20490.98}, author = {Huang, T L and Carlson, M C and Fitzpatrick, A L and Kuller, L H and Fried, L P and Zandi, P P} } @article {998, title = {NSAID use and dementia risk in the Cardiovascular Health Study: role of APOE and NSAID type.}, journal = {Neurology}, volume = {70}, year = {2008}, month = {2008 Jan 01}, pages = {17-24}, abstract = {

BACKGROUND: Epidemiologic and laboratory studies suggest that nonsteroidal antiinflammatory drugs (NSAIDs) reduce risk of Alzheimer disease (AD). We therefore investigated the association between use of NSAIDs, aspirin, and the non-NSAID analgesic acetaminophen with incidence of dementia and AD.

METHODS: Participants in the Cardiovascular Health Cognition Study included 3,229 individuals aged 65 or older, free of dementia at baseline, with information on medication use. We used Cox proportional hazards regression to estimate the association of medication use with incident all-cause dementia, AD, and vascular dementia (VaD). Additional analyses considered the NSAID-AD relationship as a function of age, presence of at least one epsilon 4 allele at APOE, race, and individual NSAIDs{\textquoteright} reported ability to reduce production of the amyloid-beta peptide variant A beta(42).

RESULTS: Use of NSAIDs was associated with a lower risk of dementia (adjusted hazard ratio or aHR 0.76, 95\% CI or CI 0.60-0.96) and, in particular, AD (aHR 0.63, CI 0.45-0.88), but not VaD (aHR 0.92, CI 0.65-1.28). No similar trends were observed with acetaminophen (aHR 0.99, CI 0.79-1.24). Closer examination suggested AD risk reduction with NSAIDs only in participants having an APOE epsilon 4 allele (aHR 0.34, CI 0.18-0.65; aHR for others 0.88, CI 0.59-1.32). There was no advantage in AD risk reduction with NSAIDs reported to selectively reduce A beta(42).

CONCLUSIONS: Results were consistent with previous cohort studies showing reduced risk of AD in NSAID users, but this association was found only in those with an APOE epsilon 4 allele, and there was no advantage for A beta(42)-lowering NSAIDs.

}, keywords = {Aged, Aged, 80 and over, Alzheimer Disease, Anti-Inflammatory Agents, Non-Steroidal, Apolipoproteins E, Cardiovascular System, Dementia, Female, Humans, Incidence, Male, Proportional Hazards Models, Prospective Studies, Risk Factors}, issn = {1526-632X}, doi = {10.1212/01.wnl.0000284596.95156.48}, author = {Szekely, C A and Breitner, J C S and Fitzpatrick, A L and Rea, T D and Psaty, B M and Kuller, L H and Zandi, P P} } @article {1155, title = {Cancer linked to Alzheimer disease but not vascular dementia.}, journal = {Neurology}, volume = {74}, year = {2010}, month = {2010 Jan 12}, pages = {106-12}, abstract = {

OBJECTIVE: To investigate whether cancer is associated with Alzheimer disease (AD) and vascular dementia (VaD).

METHODS: Cox proportional hazards models were used to test associations between prevalent dementia and risk of future cancer hospitalization, and associations between prevalent cancer and risk of subsequent dementia. Participants in the Cardiovascular Health Study-Cognition Substudy, a prospective cohort study, aged 65 years or older (n = 3,020) were followed a mean of 5.4 years for dementia and 8.3 years for cancer.

RESULTS: The presence of any AD (pure AD + mixed AD/VaD; hazard ratio [HR] = 0.41, 95\% confidence interval [CI] = 0.20-0.84) and pure AD (HR = 0.31, 95\% CI = 0.12-0.86) was associated with a reduced risk of future cancer hospitalization, adjusted for demographic factors, smoking, obesity, and physical activity. No significant associations were found between dementia at baseline and rate of cancer hospitalizations for participants with diagnoses of VaD. Prevalent cancer was associated with reduced risk of any AD (HR = 0.72; 95\% CI = 0.52-0.997) and pure AD (HR = 0.57; 95\% CI = 0.36-0.90) among white subjects after adjustment for demographics, number of APOE epsilon4 alleles, hypertension, diabetes, and coronary heart disease; the opposite association was found among minorities, but the sample size was too small to provide stable estimates. No significant association was found between cancer and subsequent development of VaD.

CONCLUSIONS: In white older adults, prevalent Alzheimer disease (AD) was longitudinally associated with a reduced risk of cancer, and a history of cancer was associated with a reduced risk of AD. Together with other work showing associations between cancer and Parkinson disease, these findings suggest the possibility that cancer is linked to neurodegeneration.

}, keywords = {Aged, Aged, 80 and over, Alzheimer Disease, Cohort Studies, Dementia, Vascular, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Hospitalization, Humans, Male, Neoplasms, Nerve Degeneration, Parkinson Disease, Prevalence, Proportional Hazards Models, Prospective Studies, Risk Assessment, Risk Factors}, issn = {1526-632X}, doi = {10.1212/WNL.0b013e3181c91873}, author = {Roe, C M and Fitzpatrick, A L and Xiong, C and Sieh, W and Kuller, L and Miller, J P and Williams, M M and Kopan, R and Behrens, M I and Morris, J C} } @article {6816, title = {Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949).}, journal = {Mol Psychiatry}, volume = {20}, year = {2015}, month = {2015 Feb}, pages = {183-92}, abstract = {

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 {\texttimes} 10(-9), MIR2113; rs17522122, P=2.55 {\texttimes} 10(-8), AKAP6; rs10119, P=5.67 {\texttimes} 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 {\texttimes} 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29\% (s.e.=5\%) and 28\% (s.e.=7\%), respectively. Using polygenic prediction analysis, ~1.2\% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 {\texttimes} 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer{\textquoteright}s disease: TOMM40, APOE, ABCG1 and MEF2C.

}, keywords = {Aged, Aged, 80 and over, Atherosclerosis, Cognition, Cognition Disorders, Cohort Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, HMGN1 Protein, Humans, Male, Middle Aged, Neuropsychological Tests, Phenotype, Polymorphism, Single Nucleotide, Scotland}, issn = {1476-5578}, doi = {10.1038/mp.2014.188}, author = {Davies, G and Armstrong, N and Bis, J C and Bressler, J and Chouraki, V and Giddaluru, S and Hofer, E and Ibrahim-Verbaas, C A and Kirin, M and Lahti, J and van der Lee, S J and Le Hellard, S and Liu, T and Marioni, R E and Oldmeadow, C and Postmus, I and Smith, A V and Smith, J A and Thalamuthu, A and Thomson, R and Vitart, V and Wang, J and Yu, L and Zgaga, L and Zhao, W and Boxall, R and Harris, S E and Hill, W D and Liewald, D C and Luciano, M and Adams, H and Ames, D and Amin, N and Amouyel, P and Assareh, A A and Au, R and Becker, J T and Beiser, A and Berr, C and Bertram, L and Boerwinkle, E and Buckley, B M and Campbell, H and Corley, J and De Jager, P L and Dufouil, C and Eriksson, J G and Espeseth, T and Faul, J D and Ford, I and Gottesman, R F and Griswold, M E and Gudnason, V and Harris, T B and Heiss, G and Hofman, A and Holliday, E G and Huffman, J and Kardia, S L R and Kochan, N and Knopman, D S and Kwok, J B and Lambert, J-C and Lee, T and Li, G and Li, S-C and Loitfelder, M and Lopez, O L and Lundervold, A J and Lundqvist, A and Mather, K A and Mirza, S S and Nyberg, L and Oostra, B A and Palotie, A and Papenberg, G and Pattie, A and Petrovic, K and Polasek, O and Psaty, B M and Redmond, P and Reppermund, S and Rotter, J I and Schmidt, H and Schuur, M and Schofield, P W and Scott, R J and Steen, V M and Stott, D J and van Swieten, J C and Taylor, K D and Trollor, J and Trompet, S and Uitterlinden, A G and Weinstein, G and Widen, E and Windham, B G and Jukema, J W and Wright, A F and Wright, M J and Yang, Q and Amieva, H and Attia, J R and Bennett, D A and Brodaty, H and de Craen, A J M and Hayward, C and Ikram, M A and Lindenberger, U and Nilsson, L-G and Porteous, D J and R{\"a}ikk{\"o}nen, K and Reinvang, I and Rudan, I and Sachdev, P S and Schmidt, R and Schofield, P R and Srikanth, V and Starr, J M and Turner, S T and Weir, D R and Wilson, J F and van Duijn, C and Launer, L and Fitzpatrick, A L and Seshadri, S and Mosley, T H and Deary, I J} } @article {6799, title = {GWAS for executive function and processing speed suggests involvement of the CADM2 gene.}, journal = {Mol Psychiatry}, volume = {21}, year = {2016}, month = {2016 Feb}, pages = {189-97}, abstract = {

To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32,070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 {\texttimes} 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 {\texttimes} 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 {\texttimes} 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 {\texttimes} 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 {\texttimes} 10(-11)) and neuron cell-cell adhesion (P-value=1.48 {\texttimes} 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.

}, issn = {1476-5578}, doi = {10.1038/mp.2015.37}, author = {Ibrahim-Verbaas, C A and Bressler, J and Debette, S and Schuur, M and Smith, A V and Bis, J C and Davies, G and Trompet, S and Smith, J A and Wolf, C and Chibnik, L B and Liu, Y and Vitart, V and Kirin, M and Petrovic, K and Polasek, O and Zgaga, L and Fawns-Ritchie, C and Hoffmann, P and Karjalainen, J and Lahti, J and Llewellyn, D J and Schmidt, C O and Mather, K A and Chouraki, V and Sun, Q and Resnick, S M and Rose, L M and Oldmeadow, C and Stewart, M and Smith, B H and Gudnason, V and Yang, Q and Mirza, S S and Jukema, J W and deJager, P L and Harris, T B and Liewald, D C and Amin, N and Coker, L H and Stegle, O and Lopez, O L and Schmidt, R and Teumer, A and Ford, I and Karbalai, N and Becker, J T and Jonsdottir, M K and Au, R and Fehrmann, R S N and Herms, S and Nalls, M and Zhao, W and Turner, S T and Yaffe, K and Lohman, K and van Swieten, J C and Kardia, S L R and Knopman, D S and Meeks, W M and Heiss, G and Holliday, E G and Schofield, P W and Tanaka, T and Stott, D J and Wang, J and Ridker, P and Gow, A J and Pattie, A and Starr, J M and Hocking, L J and Armstrong, N J and McLachlan, S and Shulman, J M and Pilling, L C and Eiriksdottir, G and Scott, R J and Kochan, N A and Palotie, A and Hsieh, Y-C and Eriksson, J G and Penman, A and Gottesman, R F and Oostra, B A and Yu, L and DeStefano, A L and Beiser, A and Garcia, M and Rotter, J I and N{\"o}then, M M and Hofman, A and Slagboom, P E and Westendorp, R G J and Buckley, B M and Wolf, P A and Uitterlinden, A G and Psaty, B M and Grabe, H J and Bandinelli, S and Chasman, D I and Grodstein, F and R{\"a}ikk{\"o}nen, K and Lambert, J-C and Porteous, D J and Price, J F and Sachdev, P S and Ferrucci, L and Attia, J R and Rudan, I and Hayward, C and Wright, A F and Wilson, J F and Cichon, S and Franke, L and Schmidt, H and Ding, J and de Craen, A J M and Fornage, M and Bennett, D A and Deary, I J and Ikram, M A and Launer, L J and Fitzpatrick, A L and Seshadri, S and van Duijn, C M and Mosley, T H} } @article {6680, title = {A novel Alzheimer disease locus located near the gene encoding tau protein.}, journal = {Mol Psychiatry}, volume = {21}, year = {2016}, month = {2016 Jan}, pages = {108-17}, abstract = {

APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer{\textquoteright}s Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 {\texttimes} 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5{\textperiodcentered}8 {\texttimes} 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1{\textperiodcentered}6 {\texttimes} 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P ⩽ 1.3 {\texttimes} 10(-8)), frontal cortex (P ⩽ 1.3 {\texttimes} 10(-9)) and temporal cortex (P⩽1.2 {\texttimes} 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 {\texttimes} 10(-6)) and temporal cortex (P=2.6 {\texttimes} 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.

}, keywords = {Alzheimer Disease, Apolipoprotein E4, Chromosomes, Human, Pair 17, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, tau Proteins}, issn = {1476-5578}, doi = {10.1038/mp.2015.23}, author = {Jun, G and Ibrahim-Verbaas, C A and Vronskaya, M and Lambert, J-C and Chung, J and Naj, A C and Kunkle, B W and Wang, L-S and Bis, J C and Bellenguez, C and Harold, D and Lunetta, K L and DeStefano, A L and Grenier-Boley, B and Sims, R and Beecham, G W and Smith, A V and Chouraki, V and Hamilton-Nelson, K L and Ikram, M A and Fi{\'e}vet, N and Denning, N and Martin, E R and Schmidt, H and Kamatani, Y and Dunstan, M L and Valladares, O and Laza, A R and Zelenika, D and Ramirez, A and Foroud, T M and Choi, S-H and Boland, A and Becker, T and Kukull, W A and van der Lee, S J and Pasquier, F and Cruchaga, C and Beekly, D and Fitzpatrick, A L and Hanon, O and Gill, M and Barber, R and Gudnason, V and Campion, D and Love, S and Bennett, D A and Amin, N and Berr, C and Tsolaki, Magda and Buxbaum, J D and Lopez, O L and Deramecourt, V and Fox, N C and Cantwell, L B and T{\'a}rraga, L and Dufouil, C and Hardy, J and Crane, P K and Eiriksdottir, G and Hannequin, D and Clarke, R and Evans, D and Mosley, T H and Letenneur, L and Brayne, C and Maier, W and De Jager, P and Emilsson, V and Dartigues, J-F and Hampel, H and Kamboh, M I and de Bruijn, R F A G and Tzourio, C and Pastor, P and Larson, E B and Rotter, J I and O{\textquoteright}Donovan, M C and Montine, T J and Nalls, M A and Mead, S and Reiman, E M and Jonsson, P V and Holmes, C and St George-Hyslop, P H and Boada, M and Passmore, P and Wendland, J R and Schmidt, R and Morgan, K and Winslow, A R and Powell, J F and Carasquillo, M and Younkin, S G and Jakobsd{\'o}ttir, J and Kauwe, J S K and Wilhelmsen, K C and Rujescu, D and N{\"o}then, M M and Hofman, A and Jones, L and Haines, J L and Psaty, B M and Van Broeckhoven, C and Holmans, P and Launer, L J and Mayeux, R and Lathrop, M and Goate, A M and Escott-Price, V and Seshadri, S and Pericak-Vance, M A and Amouyel, P and Williams, J and van Duijn, C M and Schellenberg, G D and Farrer, L A} }