Analyzing large-scale samples confirms the association between the ABCA7 rs3764650 polymorphism and Alzheimer’s disease susceptibility

Connect: liuguiyou1981@163.com

Abstract

Large-scale genome-wide association studies (GWAS) have revealed that the ABCA7 rs3764650 polymorphism (or its proxies, including rs115550680, rs3752246 and rs4147929) is associated with Alzheimer’s disease (AD) susceptibility in individuals of Caucasian ancestry. The following studies have investigated this finding in Chinese (N=633 and N=1,224), Japanese (N=1,735), Korean (N=844), African American (N=5,896) and Canadian (N=1,104) populations. However, these studies reported a weak or negligible association. We hypothesized that these negative results may have been caused by either relatively small sample sizes compared with those used for the previous GWAS in individuals of Caucasian ancestry or the genetic heterogeneity of the rs3764650 polymorphism (or its proxies) in different populations. Here, we reevaluated the association between rs3764650 and AD using large-scale samples from 18 previous studies (N=79,381, 30,590 cases and 48,791 controls) by searching PubMed, AlzGene and Google Scholar databases. Using allele, dominant, recessive and additive models, we did not identify significant heterogeneity among the 18 studies. We observed a significant association between rs3764650 and AD using the allele (P=1.76E-26, odds ratio (OR)=1.21, 95% confidence interval (CI) 1.17-1.26), dominant (P=4.00E-04, OR=1.17, 95% CI 1.07-1.28), recessive (P=3.00E-03, OR=1.43, 95% CI 1.13-1.81) and additive models (P=3.00E-03, OR=1.49, 95% CI 1.16-1.91). Collectively, our analysis further supports previous findings that the ABCA7 rs3764650 polymorphism is associated with AD susceptibility. We believe that our findings will be very useful for future genetic studies on AD.


Supplementary Figure 1. Flow chart of meta-analysis for exclusion or inclusion of individual articles




Supplementary Figure 2. Articles identified through PubMed database (2013-11-26)




Supplementary Figure 3. Articles identified through AlzGene database (2014-1-27)




Supplementary Table 1, more detailed results including gene IDs and names from pathway analysis of AD

Study
Quality Score
Population
Diagnostic criteria
     
AD cases
controls

Tan 2013 (1)

9

Chinese

NINCDS-ADRDA

The age- and gender-matched healthy control subjects were confirmed healthy and neurologically normal by medical history, general examination, laboratory examination, and Mini Mental State Examination by physicians and neurologists.

Liu 2013 (2)

8

Chinese

NINCDS-ADRDA

The control subjects were free of neurological or psychiatric disorders by medical history, physical examinations, laboratory examinations, and with Mini-Mental State Examination score over 24.

Chung 2013 (3)

8

Korean

NINCDS-ADRDA

These controls were subjects who had no neurological diseases, and no impairment in cognitive function or activities of daily living.

Miyashita 2013 (4)

9

Japanese

NINCDS-ADRDA

Elders living in an unassisted manner in the local community with no signs of dementia were used as controls.

Omoumi 2013 (5)

8

Canadian

DSM, NINCDS-ADRDA

In brief, subjects were deemed as normal or no cognitive impairment if they did not have any of the Diagnostic and Statistical Manual of Mental Disorders, version III, revised, criteria for dementia after clinical and neuropsychological assessments

Reitz 2013 (6)

8

African American

NINCDS-ADRDA

Classification of participants as African American was based on self-report using the format of the 1990 US census.

Lambert 2009 (7)

9

France

NINCDS-ADRDA, DSM or CERAD

MMSE, TICS-M, Geriatric mental schedule, cognitive performance scale, SIDAM or clinical dementia rating scale

Harold 2009 (8)

9

UK/Ireland

NINCDS-ADRDA, DSM or CERAD

MMSE, TICS-M, Geriatric mental schedule, cognitive performance scale, SIDAM or clinical dementia rating scale

Harold 2009 (8)

9

Germany

NINCDS-ADRDA, DSM or CERAD

MMSE, TICS-M, Geriatric mental schedule, cognitive performance scale, SIDAM or clinical dementia rating scale

Harold 2009 (8)

9

USA

NINCDS-ADRDA, DSM or CERAD

MMSE, TICS-M, Geriatric mental schedule, cognitive performance scale, SIDAM or clinical dementia rating scale

Hollingworth 2011 (9)

9

ADNI

NINCDS-ADRDA

Mini Mental State Examination MMSE

Hollingworth 2011 (9)

9

GERAD2

NINCDS-ADRDA, DSM or CERAD

MMSE, TICS-M, Geriatric mental schedule, cognitive performance scale, SIDAM or clinical dementia rating scale

Hollingworth 2011 (9)

9

deCODE

NINCDS-ADRDA

MMSE, TICS-M, Geriatric mental schedule, cognitive performance scale, SIDAM or clinical dementia rating scale

Hollingworth 2011 (9)

9

AD-IG

NINCDS-ADRDA, DSM or CERAD

Unscreened population

Hollingworth 2011 (9)

9

EADI2

DSM, NINCDS-ADRDA

MMSE

Hollingworth 2011 (9)

9

CHARGE

NINCDS-ADRDA, DSM or CERAD

MMSE, TICS-M, Geriatric mental schedule, cognitive performance scale, SIDAM or clinical dementia rating scale

Hollingworth 2011 (9)

9

MAYO2

NINCDS-ADRDA

MMSE, TICS-M, Geriatric mental schedule, cognitive performance scale, SIDAM or clinical dementia rating scale

Hollingworth 2011 (9)

9

ADGC

NINCDS-ADRDA, DSM or CERAD

MMSE, TICS-M, Geriatric mental schedule, cognitive performance scale, SIDAM or clinical dementia rating scale
ADNI, the Alzheimer's Disease Neuroimaging Initiative; GERAD2, The Genetic and Environmental Risk in Alzheimer's Disease 2; AD-IG, German Alzheimer’s disease Integrated Genome Research Network; ADGC, the Alzheimer’s Disease Genetic Consortium; CHARGE, The Cohorts for Heart and Aging Research in Genomic Epidemiology; EADI1, European Alzheimer’s Disease Initiative 1; Yes, the genotype numbers are available; NA, the genotype numbers are not available. NINCDS-ADRDA, the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorder Association; CERAD, the Consortium to Establish a Registry for Alzheimer's disease; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders version IV; DSM III, Diagnostic and Statistical Manual of Mental Disorders version III; The Quality Score of included studies were scored based on the criteria developed by Clark et al (10) to evaluate the quality of genetic association studies.








References
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9       Hollingworth, P., Harold, D., Sims, R., Gerrish, A., Lambert, J.C., Carrasquillo, M.M., Abraham, R., Hamshere, M.L., Pahwa, J.S., Moskvina, V. et al. (2011) Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat. Genet., 43, 429-435.
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