research article polymorphisms in the sortilin-related...

Research ArticlePolymorphisms in the Sortilin-Related Receptor 1 Gene AreAssociated with Cognitive Impairment in Filipinos

Cristine R Casingal12 Maria Luisa G Daroy12 Cynthia A Mapua12

Dianne Jane A Florendo13 Filipinas F Natividad12 and Jacqueline C Dominguez3

1 Research and Biotechnology St Lukersquos Medical Center 279 E Rodriguez Sr Boulevard 1112 Quezon City Philippines2 St Lukersquos College of Medicine William H Quasha Memorial E Rodriquez Sr Boulevard 1112 Quezon City Philippines3Memory Center Institute for Neuroscience St Lukersquos Medical Center 279 E Rodriquez Sr Boulevard 1112 Quezon City Philippines

Correspondence should be addressed to Cristine R Casingal tincasingalgmailcom

Received 6 August 2014 Revised 23 October 2014 Accepted 6 November 2014 Published 27 November 2014

Academic Editor Raymond Chuen-Chung Chang

Copyright copy 2014 Cristine R Casingal et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

BackgroundAims Sortilin-related receptor 1 (SORL1) is involved in the neuronal transport processes and plays a role in theformation of amyloid plaques This study investigated the association of 6 SORL1 single nucleotide polymorphisms (SNPs 8 910 13 19 and 23) with cognitive impairment (CI) in FilipinosMethods DNA samples from 484 subjects (100 Alzheimerrsquos Disease(AD) cases 109mild cognitive impairment (MCI) cases 18 other types of CI and 257 no dementia controls (NDC)) were genotypedusing TaqMan SNP Genotyping Assays Data Analysis Our study showed strong linkage disequilibrium in the SNPs 8 9 and 10block Our results showed that CI was significantly associated with SNPs 13 and 23 None of the SORL1 SNPs studied was associatedwith AD while SNPs 8 9 10 and 23 were associated with MCI Conclusion The findings had provided evidence that SORL1 maypredispose individuals to CI Further studies are needed to clarify the role of SORL1 in Filipinos with AD

1 Introduction

Sortilin-related receptor 1 (SORL1) is genetically linked toAlzheimerrsquos disease (AD) [1ndash7] Recent evidence indicatesthat it acts as a regulatory gatekeeper for determining theultimate destination of amyloid precursor protein (APP)[8] APP processing generates the 120573-amyloid (A120573) peptideswhich are deposited as the amyloid plaques in brains ofindividuals with AD [9]

AD was associated with the ldquoCrdquo ldquoGrdquo and ldquoCrdquo alleles atsingle nucleotide polymorphisms (SNP) 8 9 and 10 in the51015840-end of SORL1 respectively and the ldquoGrdquo and ldquoTrdquo allelesat SNPs 19 and 23 in the 31015840-end of SORL1 respectively [2]Using frozen brain tissue from autopsy-confirmed AD casesLee et al reported that some AD patients displayed low levelof SORL1 [1] These data suggest that inherited or acquiredchanges in SORL1 expression or function are mechanisticallyinvolved in causing AD

Mild cognitive impairment (MCI) refers to individualswho exhibit cognitive deficit but not dementia [10] It has an

incidence rate of 991000 person-years and an annual conver-sion rate of 10 to 12 to AD in contrast to a conversion rateof 1 to 2 in the normal elderly population [11] Sager et alreported that MCI subjects with low SORL1 expression levelswere significantly more cognitively impaired than subjectswith high levels of expressed SORL1 [10]

Currently there has been no published data on the geneticvariation of SORL1 in the Filipino population In this studywe sought to investigate the role of SORL1 (SNPs 8 9 1013 19 and 23) in Filipinos with cognitive impairment (CI)MCI and AD as well as its association with sex age and itsinteraction to Apolipoprotein E-1205764 (APOE-1205764)

2 Methodology

21 Study Population The Institutional Ethics Review Com-mittee of the St Lukersquos Medical Center approved the studyprotocol and subjects were selected based on inclusion andexclusion criteria Informed written consent was obtained

Hindawi Publishing CorporationAsian Journal of NeuroscienceVolume 2014 Article ID 891653 7 pageshttpdxdoiorg1011552014891653

2 Asian Journal of Neuroscience

rs66

8387

(SN

P 8)

rs68

9021

(SN

P 9)

rs64

1120

(SN

P 10

)

rs22

9881

3 (S

NP

13)

rs20

7004

5 (S

NP

19)

rs38

2496

8 (S

NP

23)

p15

5

p13

p12

q13

1

q13

4

q14

3

q21

q23

1

q25

Chr 11

q24

3q2

42

q24

1

q23

3

q23

2

q22

3

q22

1

q14

2

q14

1

q13

3q1

32

q12

1q1

1p1

111

p11

12p1

12

p14

1

p14

3

p15

1

p15

2p1

53

p15

4

Figure 1 Chromosome location of SORL1 and the 6 SNPs

from each subject or from reliable collateral informants whoare familiar with the subjectrsquos cognitive state

The group who evaluated the subjects consisted ofa neurologist psychologists and a nurse Every data-gathering session began with briefing to include an intakeinterview for the demographic data and medical historyusing the Philippine Neurological Association (PNA) 10-item Questionnaire for Common Neurological DiseasesClinical dementia rating (CDR) assessment of the pres-ence or absence of AD based on the National Institute ofNeurological and Communicative Disorders and Stroke andthe Alzheimerrsquos Disease and Related Disorders Association(NINCDS-ADRDA) Alzheimerrsquos criteria Montreal Cogni-tive Assessment (MOCA) Mini-Mental State Exam (MMSE-P) Disability Assessment for Dementia (DAD) Neuropsy-chiatric Inventory (NPI) and Geriatric Depression Scale(GDS) were individually administered to all the subjects

22 SORL1 Genotyping Five milliliters of whole blood inBD Vacutainer tubes with EDTA was drawn from eachsubject DNAwas extracted from the buffy coat using QiagenQIAamp DNA extraction kit Polymorphisms (numberingrelative to AP0009774) rs668387 (51432CgtT) rs689021(54631GgtA) rs641120 (64476GgtA) rs2298813 (77195GgtA)rs2070045 (131601TgtG) and rs3824968 (159433TgtA) in theSORL1 gene numbered as SNPs 8 9 10 13 19 and 23respectively were selected for testing (Figure 1) SNPs 8 9and 10 are located in the intron 6 of the gene while SNPs13 19 and 23 are located in exons 11 25 and 34 respectivelyGenotyping was performed using TaqMan SNP GenotypingAssays (Applied Biosystems)

23 Data Analysis For each SNP goodness-of-fit to Hardy-Weinberg equilibrium (HWE) was assessed using the Chi-Square test (1205942) Haploview ver 42 software developed bythe Broad Institute was used to estimate the degree of linkagedisequilibrium (LD) to detect single marker associationand to determine presence of haplotype blocks [12] Thedefault settings were used in these analyses which create 95confidence bounds onD1015840 to delineate SNP pairs in strong LD

SPSS ver 160 software was used for the association anal-ysis Differences between the genotype and allele frequenciesbetween the CI cases and no dementia controls (NDC) inFilipinos were determined by 1205942 test Univariate logisticregression was performed to determine the association of theSNPs with the CI cases The association of the SORL1 SNPswith the CI cases was indicated in odds ratio (OR) with thecorresponding 95 confidence intervals Stratified analyseswere performed to determine if associations differed betweensex age and Apolipoprotein E-1205764 (APOE-1205764) groups All testswere two-tailed and considered significant at 119875 lt 005

3 Results

31 Study Subjects A total of 484 subjects including 227(469) CI cases (100 with AD 109 with MCI and 18 withother types CI) and 257 (531) NDC were included in thisstudyThere were 335 (692) females and 149 (308) malesThe mean age was 705 plusmn 79 years old (yo) 253 (523)were le70 yo 218 (450) were lt70 yo and 13 (27) hadno recorded age APOE genotypes showed 391 (808) wereAPOE-1205764 noncarriers and 93 (192) were APOE-1205764 carriers

32 SORL1 Genotypes Theallele and genotype frequencies ofthe SORL1 SNPs (Table 1) observed in this study populationwere in HWE except for SNP 13 (1205942 = 72127) which showeda significantly higher frequency for the G allele When the 1205942of SNP 13 was computed for the NDC only the result was inHWE (1205942 = 04084)

The alleles C G G G G and A alleles of SNPs 8 9 1013 19 and 23 respectively were detected as the risk allelesfor the cognitively impaired population (Table 2) Haplotypeblock 1 showed a strong LD in SNPs 8 9 and 10 (Figure 2)This block formed a three-locus haplotype C-G-G and T-A-A However none of the haplotypes were associated with CIMCI and AD (data not shown)

33 Genetic Association Analysis Individual SNPs were ana-lyzed in the CI MCI and AD cases (Table 3) SNP 13 (119875 value

Asian Journal of Neuroscience 3

Table 1 Goodness-of-fit to HWE for the elderly Filipinos studied

SNP Observed Total 119901 obs 119902 obs 1199012 exp 2119901119902exp 1199022 exp 119875 exp 2119875119876 exp 119876 exp 1205942

8 CC TC TT56 204 224 484 03265 06735 01066 04398 04537 52 213 219 08355

9 AA GA GG224 203 57 484 06725 03275 04523 04405 01072 219 213 52 11056

10 AA GA GG224 203 57 484 06725 03275 04523 04405 01072 219 213 52 11056

13 AA GA GG7 60 417 484 00764 09236 00058 01412 08530 3 68 413 72127lowast

19 TT TG GG75 218 191 484 03802 06198 01445 04713 03842 70 228 186 09488

23 TT TA AA89 227 168 484 04184 05816 01750 04867 03383 85 235 164 06381

Legend1205942 tabulated (dF = 1 119875 = 005) 3841119901 obs observed frequency of homozygous Allele 1119902 obs observed frequency of homozygous Allele 2119875 exp expected frequency of homozygous Allele 1119876 exp expected frequency of homozygous Allele 22119875119876 exp expected frequency of heterozygoteslowastGenotypic and allelic frequencies are not in Hardy-Weinberg equilibriumIf 1205942 calculated lt 1205942 tabulated do not reject null hypothesisIf 1205942 calculated gt 1205942 tabulated reject null hypothesis

Table 2 Single marker association of SORL1 SNPs in elderlyFilipinos using Haploview

SNP number Single marker associationRisk allele 1205942 119875 value

8 C 0871 03509 G 101 031510 G 101 031513 G 349 006219 G 1015 031423 A 1687 0192

= 0041) and SNP 23 (119875 valueAA = 0016) were associated withCI SNP 8 (119875 valueTC = 0028) SNP 9 (119875 valueGA = 0034)SNP 10 (119875 valueGA = 0034) and SNP 23 (119875 valueAA = 0026119875 valueTA = 0007) showed association with MCIThe six (6)SORL1 SNPs did not show association with AD

Association of SORL1with sex and age was also evaluated(Table 4) The 6 SORL1 SNPs were not associated with theCI AD and MCI cases in the male group In the femalegroup SNPs 13 (119875 value = 0045) and 23 (119875 valueAA = 0017119875 valueTA = 0017) were associated with CI SNP 23 wasassociated with MCI (119875 value = 0033 119875 valueAA = 0011119875 valueTA = 0013) and no SORL1 SNP was associated withAD

Based on the mean age subjects were divided into twothe le70 yo and the gt70 yo groups In the le70 yo groupSNPs 19 and 23 were associated with CI (SNP 19 119875 valueGG= 0021 119875 valueTG = 0029 and SNP 23 119875 valueAA = 0025119875 valueTA = 0021) and MCI (SNP 19 119875 valueGG = 0038and SNP 23 119875 valueAA = 0021 119875 valueTA = 0018) and no

association was observed for the AD cases For the gt70 yogroup there was no association detected between the 6 SNPsand the CI MCI and AD cases

SORL1 showed no association with the APOE-1205764 carriersFor the APOE-1205764 noncarriers SORL1 was significantly asso-ciated with CI (SNP 23 119875 value = 0008 119875 valueAA = 0020119875 valueTA = 0002) SNP 8 (119875 value = 0030 119875 valueGA =0019) SNPs 9 and 10 (119875 value = 0050 119875 valueGA = 0025)SNP 19 (119875 valueGG = 0046 119875 valueTG = 0031) and SNP 23(119875 valueAA = 0017 119875 valueTA = 0002) were associated withMCI All 6 SORL1 SNPs were not significantly associated withAD (Table 3)

4 Discussion

When two or more alleles are in strong LD it means thatthese alleles are inherited together There are millions ofpolymorphisms in the human genome many of which arein LD with each other thus it is not necessary to test allpolymorphisms [12] In this study the block of SNPs 8 9and 10 was in strong equilibrium However none of thehaplotypes were associated with CIMCI and ADThis resultdid not replicate the findings from the Caribbean-HispanicIsraeli-Arab and North European datasets [2] but a similarresult was reported for the Han Chinese population [13]

Our data showed SORL1 was associated with CI Butwhen restricted to AD and MCI SORL1 was associated withMCI but not with AD SORL1 has been reported to affectAD in different population but replication studies have giveninconsistent results [3ndash7 14] The meta-analysis study byReitz and colleagues suggested that negative findings werelikely related to underpowered studies with small sample


SNP1

3

SNP1

9

SNP2

3

Block 1 (13kb)

1 2 3 4 5 6

99

99

81

81

75

34 34

3333

32

22

35

29

87SN

P8

SNP9

SNP1

0

Figure 2 Linkage disequilibrium between the SORL1 SNPs The standard Linkage disequilibrium color scheme was (D1015840LOD) with whiteto red colors representing the increasing strength of Linkage disequilibrium Block 1 (SNPs 8 9 and 10) is in strong Linkage disequilibriumresulting in haplotypes T-A-A and C-G-G with frequencies 0673 and 0323

Table 3 Association analysis of the SORL1 SNPs in Filipinos with CI MCI and AD

SORL1 SNPs CI MCI AD119875 value OR (95 CI) 119875 value OR (95 CI) 119875 value OR (95 CI)

SNP 8 0225 0076 0829TTTC 0091 1389 (0949ndash2033) 0028 1710 (1060ndash2760) 0586 1146 (0701ndash1875)CC 0857 1056 (0586ndash1904) 0858 1073 (0498ndash2320) 0914 0959 (0446ndash2060)

SNP 9 0256 0101 0829AAGA 0102 1375 (0939ndash2014) 0034 1680 (1040ndash2715) 0586 1146 (0701ndash1875)GG 0754 1098 (0612ndash1970) 0682 1171 (0552ndash2483) 0914 0959 (0446ndash2060)



SNP 19 0289 0177 0596TTTG 0120 1529 (0895ndash2611) 0075 1921 (0920ndash4014) 0317 1421 (0715ndash2825)GG 0187 1443 (0837ndash2488) 0082 1965 (0934ndash4134) 0537 1249 (0617ndash2528)

SNP 23 0055 0025 0309TTTA 0089 1861 (1123ndash3085) 0007 2708 (1319ndash5559) 0135 1637 (0858ndash3123)AA 0016 1581 (0931ndash2682) 0026 2329 (1105ndash4908) 0425 1321 (0667ndash2616)


Table 4 SORL1 SNPs analyses that showed significant association in Filipinos with CI andMCI according to sex and age groups andAPOE-1205764carriage


FemalesSNP 13 0045 0147 0169

AAGA 0464 0344 (0020ndash5974) 0214 0156 (0008ndash2919)GG 0915 0859 (0530ndash13865) 0509 0391 (0024ndash6351)

SNP 23 0052 0033 0359TTTA 0017 2156 (1144ndash4063) 0013 3566 (1300ndash9778) 0154 1783 (0804ndash3951)AA 0037 2016 (1043ndash3895) 0011 3762 (1347ndash10508) 0261 1612 (0701ndash3708)le70 years oldSNP 19 0062 0113 0288

TTTG 0029 2742 (1107ndash6792) 0059 2985 (0960ndash9281) 0125 5118 (0636ndash41202)GG 0021 2920 (1172ndash7277) 0038 3328 (1067ndash10375) 0122 5230 (0644ndash42463)


APOE-1205764 noncarriersSNP 8 0125 0030 0778

TTTC 0088 1446 (0946ndash2211) 0019 1865 (1106ndash3146) 0789 1081 (0611ndash1913)CC 0556 0815 (0412ndash1612) 0617 0792 (0318ndash1973) 0575 0771 (0310ndash1917)





sizes allelic heterogeneity or both Because AD is a complexdisease it is also likely that interaction between two or moregenes contributes to diseasersquos phenotype

The relationship between SORL1 and MCI remainsunclear but may suggest that MCI can be modulated bySORL1 like how it is modulated by APOE Whitehair etal reported the influence of APOE-1205764 genotype on ratesof cognitive decline in MCI They found out that APOE-1205764 carriers had significantly more rapid decline in cognitive

and functional performance [15] On the other hand SORL1expression in individuals with MCI was heterogeneous suchthat someMCI cases had SORL1 expression similar to healthycontrols while it was reduced in others to levels similar tothose seen in AD [10 16] These reports indicate that SORL1and APOE have similar effect on the cognition of individualswith MCI

SORL1 (SNP 23) was significantly associated with thefemale sex in this study A previous report showed a similar


result wherein SORL1 (SNP 4) was also associated with thefemale sex [6] For individuals over the age of 80 womenare at slightly higher risk of AD while men may be at higherrisk of vascular dementia [17] Prevalence of MCI in maleswas higher than that in females however the transition inwomen from normal cognition to dementia is more abrupt inwomen [18] The importance of estrogen receptor-mediatedneuroprotection in females was cited as a plausible factor incognition [19]These reports suggest the possible sex-specificinterplay of risk factors disease course and survival in thisdisease

Aswe growolder our cognitive abilities gradually declineFor AD age is a major risk factor [2] Around 50 ofall people more than 85 years old suffer from AD [20]Interestingly no association was observed in the gt70 yogroup with CIMCI and AD Interestingly the le70 yo groupwas associated with SORL1 in the CI and MCI cases Wehypothesized that the sample size subject heterogeneity andage range in our groupings may be the reasons why we werenot able to replicate the positive results of Rogaeva et al

The association of SORL1with CI female sex andle70 yogroup elucidated in this studymay indicate the early effects ofthis gene in the development of CI leading to dementia

It has been suggested that SORL1 activity is influenced byAPOE [20] Alterations in the three-dimensional structureand binding properties of APOE in the APOE-1205764 isoformmay result in changes in the interaction between SORL1 andAPOE that could affect the capacity of SORL1 to bind toAPP Thus the APOE isoform may have a modifying effecton the association of SORL1 and APOE specifically effects ofdistinct SORL1 SNPsmay beweakened by theAPOE-1205764 alleleSeveral studies showed association of SORL1 SNPs with ADin APOE-1205764 noncarriers [7 21]

In this study significant association of the SORL1 SNPswas detected with MCI and CI in APOE-1205764 noncarriers butnot with AD To determine possible interaction of SORL1 andAPOE we also tested the association of APOE-1205764 allele withCI MCI and ADThe result showed that APOE-1205764 allele wasassociated with AD (119875 value = 0017) APOE-1205764 allele wasnot associated with CI (119875 value = 0140) and MCI (119875 value= 0870) Based on this result it could be possible that thepresence of APOE-1205764 allele may have masked the effect ofthe SORL1 in AD These data support the role of SORL1 inADpathogenesis contributing to an increased risk to CI evenwhen the APOE-1205764 allele is not present

Because SORL1 plays a crucial role in APP processing itis a reliable gene that could help fill up missing links in thecomplex genetics of AD and other CIs This study providesbaseline information on the possible contribution of SORL1 toincreased risk of CI in Filipinos Although no association wasobserved between the SORL1 and AD our findings provideevidence that SORL1may signal a predisposition to cognitiveimpairment in Filipinos

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This study was funded by a grant from the Research andBiotechnology the St Lukersquos Medical Center Quezon CityPhilippines The authors are grateful for the assistance givenby the Memory Center of the St Lukersquos Medical Centerthe St Lukersquos College of Medicine and the Senior CitizenCommunity of Marikina City Philippines

References

[1] J H Lee R Cheng L S Honig J-P G Vonsattel L Clark andRMayeux ldquoAssociation between genetic variants in SORL1 andautopsy-confirmed Alzheimer diseaserdquo Neurology vol 70 no11 pp 887ndash889 2008

[2] E Rogaeva Y Meng J H Lee et al ldquoThe neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimerdiseaserdquo Nature Genetics vol 39 no 2 pp 168ndash177 2007

[3] N Shibata T OhnumaH Baba S Higashi K Nishioka andHArai ldquoGenetic association between SORL1 polymorphisms andAlzheimerrsquos disease in a Japanese populationrdquo Dementia andGeriatric Cognitive Disorders vol 26 no 2 pp 161ndash164 2008

[4] C Reitz R Cheng E Rogaeva et al ldquoMeta-analysis of theassociation between variants in SORL1 and Alzheimer diseaserdquoArchives of Neurology vol 68 no 1 pp 99ndash106 2011

[5] K Bettens N Brouwers S Engelborghs P P De Deyn C VanBroechoven and K Sleegers ldquoSORL1 is genetically associatedwith increased risk for late-onset Alzheimer disease in theBelgian populationrdquo Human Mutation vol 29 no 5 pp 769ndash770 2008

[6] E Cellini A Tedde S Bagnoli et al ldquoImplication of sex andSORL1 variants in Italian patients with Alzheimer diseaserdquoArchives of Neurology vol 66 no 10 pp 1260ndash1266 2009

[7] R Kimura M Yamamoto T Morihara et al ldquoSORL1 isgenetically associated with Alzheimerrsquos disease in Japanesepopulationrdquo Neuroscience Letters vol 461 no 2 pp 177ndash1802009

[8] R Mayeux and P St George-Hyslop ldquoAlzheimerrsquos disease 2007mind the trafficrdquo The Lancet Neurology vol 7 no 1 pp 2ndash32008

[9] H Zheng and E H Koo ldquoThe amyloid precursor proteinbeyond amyloidrdquo Molecular Neurodegeneration vol 1 no 1article 5 2006

[10] K L Sager J Wuu S E Leurgans et al ldquoNeuronal LR11SorLAexpression is reduced in mild cognitive impairmentrdquo Annals ofNeurology vol 62 no 6 pp 640ndash647 2007

[11] C Reitz C Brayne and R Mayeux ldquoEpidemiology of Alz-heimer diseaserdquoNature Reviews Neurology vol 7 no 3 pp 137ndash152 2011

[12] C-H Lin Linkage disequilibriummeasures [Master of Science inStatistics] UCLA 2005

[13] E K Tan J Lee C P Chen Y Y Teo Y Zhao and W LLee ldquoSORL1 haplotypes modulate risk of Alzheimerrsquos disease inChineserdquo Neurobiology of Aging vol 30 no 7 pp 1048ndash10512009

[14] R LMinster S T DeKosky andM I Kamboh ldquoNo associationof SORL1 SNPs with Alzheimerrsquos diseaserdquo Neuroscience Lettersvol 440 no 2 pp 190ndash192 2008

[15] D C Whitehair A Sherzai J Emond et al ldquoInfluence of apol-ipoprotein e 1205764 on rates of cognitive and functional decline in


mild cognitive impairmentrdquo Alzheimerrsquos and Dementia vol 6no 5 pp 412ndash419 2010

[16] K E Grear I-F Ling J F Simpson et al ldquoExpression of SORL1and a novel SORL1 splice variant in normal and Alzheimersdisease brainrdquo Molecular Neurodegeneration vol 4 article 462009

[17] AlzheimerrsquosAssociation ldquoAlzheimerrsquos disease facts andfiguresrdquoAlzheimerrsquos and Dementia vol 6 pp 1ndash74 2010

[18] R C Petersen R O Roberts D S Knopman et al ldquoPrevalenceof mild cognitive impairment is higher in men theMayo ClinicStudy of Agingrdquo Neurology vol 75 no 10 pp 889ndash897 2010

[19] A Peri andM Serio ldquoEstrogen receptor-mediated neuroprotec-tion the role of the Alzheimerrsquos disease-related gene seladin-1rdquoNeuropsychiatric Disease and Treatment vol 4 no 4 pp 817ndash824 2008

[20] R Perneczky P Alexopoulos T Eisele H Forstl and A KurzldquoDoes the apolipoprotein E genotype influence amyloid precur-sor protein sorting by sortilin-related receptor implications forAlzheimerrsquos diseaserdquo Medical Hypotheses and Research vol 6pp 19ndash24 2010

[21] J H Lee N Shibata R Cheng and RMayeux ldquoPossible associ-ation between SORL1 and Alzheimerrsquos diseaserdquo Dementia andGeriatric Cognitive Disorders vol 26 p 48 2008

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


BioMed Research International


Research and TreatmentSchizophrenia

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


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Parkinsonrsquos Disease


Research and TreatmentAutism

Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


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Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


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Computational and Mathematical Methods in Medicine

Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


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StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neurodegenerative Diseases


Journal of

Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


rs66

8387

(SN

P 8)

rs68

9021

(SN

P 9)

rs64

1120

(SN

P 10

)

rs22

9881

3 (S

NP

13)

rs20

7004

5 (S

NP

19)

rs38

2496

8 (S

NP

23)

p15

5

p13

p12

q13

1

q13

4

q14

3

q21

q23

1

q25

Chr 11

q24

3q2

42

q24

1

q23

3

q23

2

q22

3

q22

1

q14

2

q14

1

q13

3q1

32

q12

1q1

1p1

111

p11

12p1

12

p14

1

p14

3

p15

1

p15

2p1

53

p15

4

Figure 1 Chromosome location of SORL1 and the 6 SNPs

from each subject or from reliable collateral informants whoare familiar with the subjectrsquos cognitive state

The group who evaluated the subjects consisted ofa neurologist psychologists and a nurse Every data-gathering session began with briefing to include an intakeinterview for the demographic data and medical historyusing the Philippine Neurological Association (PNA) 10-item Questionnaire for Common Neurological DiseasesClinical dementia rating (CDR) assessment of the pres-ence or absence of AD based on the National Institute ofNeurological and Communicative Disorders and Stroke andthe Alzheimerrsquos Disease and Related Disorders Association(NINCDS-ADRDA) Alzheimerrsquos criteria Montreal Cogni-tive Assessment (MOCA) Mini-Mental State Exam (MMSE-P) Disability Assessment for Dementia (DAD) Neuropsy-chiatric Inventory (NPI) and Geriatric Depression Scale(GDS) were individually administered to all the subjects

22 SORL1 Genotyping Five milliliters of whole blood inBD Vacutainer tubes with EDTA was drawn from eachsubject DNAwas extracted from the buffy coat using QiagenQIAamp DNA extraction kit Polymorphisms (numberingrelative to AP0009774) rs668387 (51432CgtT) rs689021(54631GgtA) rs641120 (64476GgtA) rs2298813 (77195GgtA)rs2070045 (131601TgtG) and rs3824968 (159433TgtA) in theSORL1 gene numbered as SNPs 8 9 10 13 19 and 23respectively were selected for testing (Figure 1) SNPs 8 9and 10 are located in the intron 6 of the gene while SNPs13 19 and 23 are located in exons 11 25 and 34 respectivelyGenotyping was performed using TaqMan SNP GenotypingAssays (Applied Biosystems)

23 Data Analysis For each SNP goodness-of-fit to Hardy-Weinberg equilibrium (HWE) was assessed using the Chi-Square test (1205942) Haploview ver 42 software developed bythe Broad Institute was used to estimate the degree of linkagedisequilibrium (LD) to detect single marker associationand to determine presence of haplotype blocks [12] Thedefault settings were used in these analyses which create 95confidence bounds onD1015840 to delineate SNP pairs in strong LD

SPSS ver 160 software was used for the association anal-ysis Differences between the genotype and allele frequenciesbetween the CI cases and no dementia controls (NDC) inFilipinos were determined by 1205942 test Univariate logisticregression was performed to determine the association of theSNPs with the CI cases The association of the SORL1 SNPswith the CI cases was indicated in odds ratio (OR) with thecorresponding 95 confidence intervals Stratified analyseswere performed to determine if associations differed betweensex age and Apolipoprotein E-1205764 (APOE-1205764) groups All testswere two-tailed and considered significant at 119875 lt 005

3 Results

31 Study Subjects A total of 484 subjects including 227(469) CI cases (100 with AD 109 with MCI and 18 withother types CI) and 257 (531) NDC were included in thisstudyThere were 335 (692) females and 149 (308) malesThe mean age was 705 plusmn 79 years old (yo) 253 (523)were le70 yo 218 (450) were lt70 yo and 13 (27) hadno recorded age APOE genotypes showed 391 (808) wereAPOE-1205764 noncarriers and 93 (192) were APOE-1205764 carriers

32 SORL1 Genotypes Theallele and genotype frequencies ofthe SORL1 SNPs (Table 1) observed in this study populationwere in HWE except for SNP 13 (1205942 = 72127) which showeda significantly higher frequency for the G allele When the 1205942of SNP 13 was computed for the NDC only the result was inHWE (1205942 = 04084)

The alleles C G G G G and A alleles of SNPs 8 9 1013 19 and 23 respectively were detected as the risk allelesfor the cognitively impaired population (Table 2) Haplotypeblock 1 showed a strong LD in SNPs 8 9 and 10 (Figure 2)This block formed a three-locus haplotype C-G-G and T-A-A However none of the haplotypes were associated with CIMCI and AD (data not shown)

33 Genetic Association Analysis Individual SNPs were ana-lyzed in the CI MCI and AD cases (Table 3) SNP 13 (119875 value




8 CC TC TT56 204 224 484 03265 06735 01066 04398 04537 52 213 219 08355

9 AA GA GG224 203 57 484 06725 03275 04523 04405 01072 219 213 52 11056

10 AA GA GG224 203 57 484 06725 03275 04523 04405 01072 219 213 52 11056

13 AA GA GG7 60 417 484 00764 09236 00058 01412 08530 3 68 413 72127lowast

19 TT TG GG75 218 191 484 03802 06198 01445 04713 03842 70 228 186 09488

23 TT TA AA89 227 168 484 04184 05816 01750 04867 03383 85 235 164 06381




8 C 0871 03509 G 101 031510 G 101 031513 G 349 006219 G 1015 031423 A 1687 0192






4 Discussion




SNP1

3

SNP1

9

SNP2

3

Block 1 (13kb)

1 2 3 4 5 6

99

99

81

81

75

34 34

3333

32

22

35

29

87SN

P8

SNP9

SNP1

0













FemalesSNP 13 0045 0147 0169
























Acknowledgments


References




































Neural Plasticity










Psychiatry Journal









Journal of





8 CC TC TT56 204 224 484 03265 06735 01066 04398 04537 52 213 219 08355

9 AA GA GG224 203 57 484 06725 03275 04523 04405 01072 219 213 52 11056

10 AA GA GG224 203 57 484 06725 03275 04523 04405 01072 219 213 52 11056

13 AA GA GG7 60 417 484 00764 09236 00058 01412 08530 3 68 413 72127lowast

19 TT TG GG75 218 191 484 03802 06198 01445 04713 03842 70 228 186 09488

23 TT TA AA89 227 168 484 04184 05816 01750 04867 03383 85 235 164 06381




8 C 0871 03509 G 101 031510 G 101 031513 G 349 006219 G 1015 031423 A 1687 0192






4 Discussion




SNP1

3

SNP1

9

SNP2

3

Block 1 (13kb)

1 2 3 4 5 6

99

99

81

81

75

34 34

3333

32

22

35

29

87SN

P8

SNP9

SNP1

0













FemalesSNP 13 0045 0147 0169
























Acknowledgments


References




































Neural Plasticity










Psychiatry Journal









Journal of



SNP1

3

SNP1

9

SNP2

3

Block 1 (13kb)

1 2 3 4 5 6

99

99

81

81

75

34 34

3333

32

22

35

29

87SN

P8

SNP9

SNP1

0













FemalesSNP 13 0045 0147 0169
























Acknowledgments


References




































Neural Plasticity










Psychiatry Journal









Journal of





FemalesSNP 13 0045 0147 0169
























Acknowledgments


References




































Neural Plasticity










Psychiatry Journal









Journal of











Acknowledgments


References




































Neural Plasticity










Psychiatry Journal









Journal of






















Neural Plasticity










Psychiatry Journal









Journal of


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