International Journal of Alzheimer’s Disease

International Journal of Alzheimer’s Disease / 2012 / Article

Research Article | Open Access

Volume 2012 |Article ID 245038 | 18 pages | https://doi.org/10.1155/2012/245038

Japanese Alzheimer’s Disease and Other Complex Disorders Diagnosis Based on Mitochondrial SNP Haplogroups

Academic Editor: Bruce G. Pollock
Received11 Jan 2012
Revised14 Mar 2012
Accepted30 Mar 2012
Published17 Jul 2012

Abstract

This paper first explains how the relations between Japanese Alzheimer’s disease (AD) patients and their mitochondrial SNP frequencies at individual mtDNA positions examined using the radial basis function (RBF) network and a method based on RBF network predictions and that Japanese AD patients are associated with the haplogroups G2a and N9b1. It then describes a method for the initial diagnosis of Alzheimer’s disease that is based on the mtSNP haplogroups of the AD patients. The method examines the relations between someone’s mtDNA mutations and the mtSNPs of AD patients. As the mtSNP haplogroups thus obtained indicate which nucleotides of mtDNA loci are changed in the Alzheimer’s patients, a person’s probability of becoming an AD patient can be predicted by comparing those mtDNA mutations with that person’s mtDNA mutations. The proposed method can also be used to diagnose diseases such as Parkinson’s disease and type 2 diabetes and to identify people likely to become centenarians.

1. Introduction

Mitochondria are essential cytoplasmic organelles generating cellular energy in the form of adenosine triphosphate by oxidative phosphorylation. Because most cells contain hundreds of mitochondria, each having multiple copies of their mitochondrial DNA (mtDNA), each cell contains several thousand mtDNA copies. The mutation rate for mtDNA is very high, and when mtDNA mutations occur, the cells contain a mixture of wild-type and mutant mtDNAs. As the mutations accumulate, the percentage of mutant mtDNAs increases and the amount of energy produced within the cell can decline until it falls below the level necessary for the cell to function normally. When this bioenergetic threshold is crossed, disease symptoms appear and become progressively worse. Mitochondrial diseases encompass an extraordinary assemblage of clinical problems, usually involving tissues that require large amounts of energy, such as those in the heart, skeletal muscle, kidney, and endocrine glands [13].

Although there are reports that mtDNA mutations are related to aging and a wide variety of diseases—such as Alzheimer’s disease (AD), Parkinson’s disease (PD), type 2 diabetes (T2D) disease, and various kinds of cancer [420]—those reports focus on the amino acid replacements caused by mtDNA mutations. Mitochondrial functions can of course be affected directly by amino acid replacements, but they can also be affected indirectly by mutations in mtDNA control regions. It is, therefore, important to examine the relations between all mtDNA mutations and disease patients or centenarians.

In the work reported here, the relations between Japanese AD patients and their mitochondrial single nucleotide polymorphism (mtSNP) frequencies were first analyzed using a method based on radial basis function (RBF) networks [21, 22] and a method based on RBF network predictions [23]. The mtSNP haplogroups thus obtained were then used to predict whether or not someone will get Alzheimer’s disease. It is also shown here that this diagnosis method based on the relations between PD patients, T2D patients, or centenarians and the mtSNPs of their haplogroups can also be used to diagnose other diseases and identify individuals likely to live a long time. The haplogroups described here are different from those reported previously [15, 16, 24, 25] and the proposed diagnosis method is the first one based on these haplogroups.

2. Materials and Methods

2.1. mtSNPs for Japanese People

Tanaka et al. sequenced the complete mitochondrial genomes of 672 Japanese individuals to construct an East Asia mitochondrial DNA (mtDNA) phylogeny [26]. Using these sequences and other published Asian sequences, they constructed the phylogenetic tree for macrohaplogroups M and N [2628]. In the present study, the mtSNPs in various classes of people—96 Japanese Alzheimer’s disease (AD) patients (20 males and 76 females, mean age: years; range 47 to 93 years), 96 Japanese Parkinson’s disease (PD) patients (43 males and 53 females, mean age: years; range 39 to 81 years), 96 Japanese type 2 diabetes (T2D) patients (54 males and 42 females, mean age: years; range 43 to 65 years), 96 Japanese T2D patients with angiopathy (48 males and 48 females, mean age: years; range 43 to 92 years), 96 Japanese centenarians (30 males and 66 females, mean age: year; range 95 to 105 years), 96 Japanese healthy non-obese young males (96 males, mean age: years; range 18 to 25 years), and 96 Japanese healthy obese young males (96 males, mean age: years; range 18 to 25 years)—were obtained from the GiiB Human Mitochondrial Genome Polymorphism Database (http://mtsnp.tmig.or.jp/mtsnp), and the mtSNPs in 112 Japanese semi-supercentenarians (16 males and 96 females, mean age: years; range 105 to 115 years) were obtained from the report by Bilal et al. [25]. This paper, therefore, analyzed the mitochondrial genomes of 784 Japanese individuals although only 480 individuals were examined in Takasaki 2009 [23].

2.2. mtSNP Classification Using an RBF Network

The mtSNP classification for AD patients was examined using a radial basis function (RBF) and a method based on RBF network predictions. The RBF network is an artificial network used in supervised learning problems such as regression, classification, and time series prediction. In supervised learning, a function is inferred from examples (a training set) that a teacher supplies. The elements in the training set are paired values of the independent (input) variable and dependent (output) variable.

The RBF network shown in Figure 1 was learned from the training set as the mtSNPs of the AD patients were regarded as correct and the mtSNPs of other seven classes of people (i.e., PD patients, T2D patients, T2D patients with angiopathy, centenarians, semi-supercentenarians, obese young males, and non-obese young males) were regarded as incorrect. The mtSNP classifications for the other seven classes were carried out in the same way as that for the AD patients (Figure 1).

The mitochondrial genome sequences of the AD patients were partitioned into two sets: training data comprising the sequences of 64 of the 96 AD patients, and validation data comprising the sequences of the other 32 AD patients. The classification processes were carried out in two phases, training and validation, described in detail elsewhere [29].

2.3. Classification Based on Probabilities Predicted by the RBF Network

Since an RBF network can predict the probabilities that persons with certain mtSNPs belong to certain classes, these predicted probabilities were used to identify mtSNP features. Then other mtSNPs useful for distinguishing between the members in different classes were identified by examining the relations between individual mtSNPs and the persons with high predicted probabilities of belonging to one of these classes. Classification based on the probabilities predicted by the RBF network is carried out in the following way [23].(1)Select the target class to be analyzed.(2)Rank individuals according to their predicted probabilities of belonging to the target class.(3)Either select individuals whose probabilities are greater than a certain value or select the desired number of individuals and set them as a modified cluster.

2.4. Diagnosis of Various Diseases and Longevity

As the proposed analysis method can predict a person’s mtSNP constitution and probability of being an AD patient, PD patient, T2D patient, T2D patient with angiopathy, or a centenarian, it can be useful in the initial diagnoses of various diseases or longevity. The diagnosis can be checked in the following way.(1)Generate a table indicating the relations between mtDNA mutations and haplogroups of specified disease patients (e.g., AD patients, PD patients, T2D patients, T2D patients with angiopathy) or centenarians.(2)Examine the ratio of the mtDNA mutations of a certain person to the SNPs of the haplogroups for the specified disease patients or centenarians.(3)If the ratio is greater than a certain value (i.e., 0.8), the probability of that person’s getting the specified disease or becoming a centenarian is higher than that of ordinary healthy persons.

Users can easily use the proposed method by using commercial or free RBF tools and Excel programs.

3. Results and Discussion

3.1. Associations between Japanese Haplogroups and mtSNPs of the AD Patients

When the mtSNPs of the AD patients were classified by the RBF-based method described above, eight mtSNP clusters were obtained. The average predicted probabilities of the people in these clusters becoming the AD patients are listed in Table 1. Since there were big differences among the predicted probabilities of 17 individuals in the cluster 1, the 15 individuals with the highest predicted probabilities of becoming AD patients were selected using the modified classification method, and their nucleotide distributions at individual mtDNA positions were examined. After that, the relations between Japanese haplogroups and the mtSNPs for the AD patients were examined [2628]. The associations between the haplogroups and mtSNPs for the AD patients are shown in Figure 2(a). The features of associations for the AD patients were L3-M-G2a (53%) and L3-N-N9b1 (20%).


Classification IDNumber of personsPredicted probability (%)

AD patients11788.3
23345.6
33644.4
42740.7
53619.4
6390
7320
83030

PD patients11060
21656.3
31553.3
41741.2
5633.3
61330.8
71827.8
82119
95915.3
101711.8
112611.5
121010
13137.7
14244.2
15593.4
1690
17310
1890
19600
2060
21840

T2D patients11450
24835.4
31735.3
43129
53023.3
64017.5
73212.5
8368.3
9336.1
10474.3
11320
12890
13740

11681.3
T2D patients with angiopathy21957.9
33551.4
43943.6
51414.3
6329.4
71060
82620

Centenarians13966.7
2955.6
32642.3
41741.1
51540
62213.6
72313
8287.1
9205
1070
11220
121130
13850
14970

Semi-supercentenarians11266.7
22948.3
34835.4
42630.8
53020
65516.4
74714.9
83013.3
9244.2
10991
11240
12990

12857.1
21154.5
31250
4540
51637.5
6633.3
72321.7
Healthy non-obese young males81020
96217.7
101010
11128.3
12248.3
13277.4
14195.3
15293.4
16270
17150
18720
191150

Obese young males13262.5
23852.6
32931
42429.2
52828.6
6970
72750

To compare the mitochondrial haplogroups of the AD patients with those of other classes of Japanese people, the relations between seven classes of Japanese people (Japanese PD patients, T2D patients, T2D patients with angiopathy, centenarians, semi-supercentenarians, non-obese young males, and obese young males) and their mtSNPs were also examined using the same modified method. The other seven associations between the haplogroups and mtSNPs for the PD patients, the T2D patients, the T2D patients with angiopathy, the centenarians, the semi-supercentenarians, the non-obese young males, and the obese young males are shown in Figures 2(b)2(h). The relations among the haplogroups for all classes of people are listed in Table 2, from which it is clear that the haplogroups of the AD patients are different from those of other classes of Japanese people.


AD patientsPD patientsT2D patientsT2D patients with angiopathyCentenariansSemi-super- centenariansNon-obese young malesObese young males

MM17%
M7a1a13%13%
M7b213%47%
M8a27%
G1a20%
G2a53%13%
DD4b120%
D4b2a27%
D4b2b40%13%20%
D4g33%

B4c113%
B4c1a40%
B4c1b17%
B4c1c113%
B4b/d/e7%
NB4e
B5b27%13%27%
F127%
N9a20%27%
N9a247%
N9b120%

3.2. Alzheimer’s Disease Diagnosis Based on the mtSNP Haplogroups

The relations between mtDNA mutations and the haplogroups of the AD patients shown in Figure 2(a) imply that the probability of becoming an AD patient is predicted by a person’s mtSNP constitution. That is, if the haplogroups of a person are identified by examining his/her mtDNA mutations, that person’s probability of becoming an AD patient might be also predicted by examining the relations between the mtDNA mutations and the mtSNPs of the haplogoups identified using the method described in Section 2. The relations between mtDNA loci and mtDNA mutations of the haplogroups G2a and N9b1 for the AD patients are listed in Table 3(a), and it is easy to check the relations between the mtDNA mutations and the mtSNPs of the haplogroups G2a and N9b1 by using that table. If, for example, someone’s mtDNA mutations were A, G, C, T, A, G, A, G, A, C, and C at the loci 709, 4833, 5108, 5601, 7600, 9377, 9575, 13563, 14569, 16362, and 16519, one could see in Table 3(a) that those are all the mtDNA mutations of the haplogroup G2a except the ones at mtDNA positions 14200 and 16278. This implies that the person with those 11 mutations has a high probability of becoming an AD patient because the ratio of the mtDNA mutations to the SNPs of the haplogroup G2a is 0.84 (11/13).

(a)

mtDNA locusNormal nucleotidemtDNA mutationAD patients
G2aN9b1

709GAA
4833AGG
5108TCC
5147GAA
5417GAA
5601CTT
7600GAA
9377AGG
9575GAA
10607CTT
11016GAA
13183AGG
13563AGG
14200TCC
14569GAA
14893AGG
16278CTT
16362TCC
16519TCC

(b)

mtDNA locusNormal nucleotidemtDNA mutationPD patients
M7a1aG1aB5bN9a

150CTTT
204TCC
709GAA
1598GAA
2626TCC
2772CTT
4386TCC
4958AGG
5231GAA
5417GAA
7867CTT
8020GAA
8584GAA
9950TCC
11017TCC
11084AGG
12358AGG
12361AGG
12372GAA
12771GAA
14364GAA
15223CTT
15323GAA
15851AGG
15927GAA
16140TCC
16209TCC
16243TCC
16257CAA
16261CTT
16324TCC
16519TCC

(c)

mtDNA locusNormal nucleotidemtDNA mutationT2D patients
M8aD4b2bB5b

194CTT
204TCC
709GAA
1382ACC
1598GAA
3010GAA
4715AGG
4883CTT
5178CAA
6179GAA
7196CAA
8020GAA
8414CTT
8584GAAA
8684CTT
8829CTT
8964CTT
9296CTT
9824TAA
9950TCC
12361AGG
14470TCC
14605AGG
14668CTT
15223CTT
15487ATT
15508CTT
15662AGG
15851AGG
15927GAA
16140TCC
16243TCC
16298TCC
16319GAA
16519TCCC

(d)

mtDNA locusNormal nucleotidemtDNA mutationT2D patients with angiopathy
G2aD4b1N9a2

150CTT
709GAA
3010GAA
4833AGG
4883CTT
5108TCC
5178CAA
5231GAA
5417GAA
5601CTT
7600GAA
8020GAA
8414CTT
9377AGG
9575GAA
10181CTT
12358AGG
12372GAA
13563AGG
14569GAA
14668CTT
15440TCC
15951AGG
16172TCC
16257CAA
16261CTT
16278CTT
16319GAA
16362TCCC
16519TCCCC

(e)

mtDNA locusNormal nucleotidemtDNA mutationCentenarians
M7b2D4b2aB5b

150CTT
199TCC
204TCC
709GAA
1382ACC
1598GAA
3010GAA
4048GAA
4071CTT
4164AGG
4883CTT
5178CAA
5351AGG
5460GAA
6455CTT
6680TCC
7684TCC
7853GAA
8020GAA
8251GAA
8414CTT
8584GAA
8829CTT
8964CTT
9824TAA
9824TCC
9950TCC
10104CTT
10345TCC
12361AGG
12405CTT
12705CTT
12811TCC
14668CTT
15223CTT
15508CTT
15662AGG
15851AGG
15927GAA
16129GAA
16140TCC
16223CTT
16243TCC
16297TCC
16298TCC
16362TCC
16519TCCC

(f)

mtDNA locusNormal nucleotidemtDNA mutationSemi-supercentenarians
M1B4c1aB4c1b1B4c1c1F1

150CTTT
195TCCC
709GAA
1119TCCCC
1621TCCCC
3497CTTT
3970CTT
6392TCC
6962GAA
10310GAAA
10398AGG
10609GAA
12406GAA
12705CTTTTT
12802CTT
13928GCC
15346GAA
16140TCC
16217TCCCC
16223CTTTTT
16249TCC
16274GAA
16311TCCC
16519TCCCCC

(g)

mtDNA locusNormal nucleotidemtDNA mutationNon-obese young males
D4b2bD4gB4b/d/eN9a

150CTT
194CTT
827AGG
1382ACC
3010GAA
4343AGG
4883CTTT
5178CAAA
5231GAA
5417GAA
8020GAA
8414CTT
8701AGG
8964CTT
9296CTT
9824TAA
12358AGG
12372GAA
12705CTT
13104AGG
14668CTTT
15518CTT
15535CTT
16217TCC
16223CTT
16257CAA
16261CTT
16278CTT
16362TCCC
16519TCCCCC

(h)

Obese young males
mtDNA locusNormal nucleotidemtDNA mutationM7a1aM7b2D4b2bB4c1

150CTT
194CTT
199TCC
709GAA
1119TCC
1382ACC
2626TCC
2772CTT
3010GAA
3497CTT
4048GAA
4071CTT
4164AGG
4386TCC
4883CTT
4958AGG
5178CAA
5351AGG
5460GAA
6455CTTT
6680TCC
7684TCC
7853GAA
8020GAA
8964CTT
9296CTT
9824TAA
10345TCC
12405CTT
12705CTT
12771GAA
12811TCC
14668CTT
15346GAA
16129GAA
16209TCC
16217TCC
16223CTT
16297TCC
16298TCC
16324TCC
16362TCC
16519TCCC

This initial diagnosis method can be applied for other diseases or for the likelihood of longevity. The relations between the mtDNA mutations and haplogroups of the PD patients, T2D patients, T2D patients with angiopathy, centenarians, semi-supercentenarians, non-obese young males, and obese young males are listed in Tables 3(b)–3(h). In case of PD, one can see in Table 3(b) that if a person’s mtDNA mutations were C, A, A, A, C, G, G, T, A, and C at the loci 204, 709, 1598, 8584, 9950, 12358, 12361, 15223, 15927, and 16140, that person would have a high probability of becoming a PD patient because the ratio of the mtDNA mutations to the SNPs of the haplogroup B5b is 0.83 (10/12). Similarly, one can see in Table 3(c) that if a person’s mtDNA mutations were T, C, A, T, A, A, T, T, A, T, and C at loci 194, 1382, 3010, 4883, 5178, 8020, 8414, 8964, 9824, 14668, and 16519, that person would have high a probability of becoming a T2D patient because the ratio of the mtDNA mutations to the SNPs of the haplogroup D4b2b is 0.846 (11/13). The likelihood of longevity can also be diagnosed by the proposed method. One sees in Table 3(e) that if a person’s mtDNA mutations were C, C, A, T, A, A, T, T, A, T, T, C, and C at the mtDNA loci 199, 1382, 3010, 4883, 5178, 8020, 8414, 8964, 9824, 10104, 14668, 16362, and 16519, that person would have a high probability of becoming a centenarian because the ratio of the mtDNA mutations to the SNPs of the haplogroup D4b2a is 0.867 (13/15).

3.3. Differences between Statistical Technique and the Modified RBF Method

Although the haplogroups of the AD patients were obtained by the modified RBF method, there are clear differences between the previously reported statistical technique and the method described here. The differences between standard statistical technique and the proposed method are listed in Table 4. In the statistical technique, the analysis of odds ratios or relative risks is based on the relative relations between target and control data at each polymorphic mtDNA locus. In the modified RBF method, on the other hand, clusters indicating predicted probabilities are examined on the basis of the RBF using correct and incorrect data for the entire polymorphic mtDNA loci. The statistical technique determines characteristics of haplogroups using independent mtDNA polymorphisms that indicate high odds ratios, whereas the modified RBF method determines them by checking individuals with high predicted probabilities. This means that the statistical technique uses the results of independent mutation positions, whereas the modified RBF method uses the results of entire mutation positions. As there are the differences between the two methods, which method is better depends on future research.


Statistical techniqueProposed method

TechniqueRelative relations between target and normal dataSupervised learning (RBF) by using correct and incorrect data
Analysis positionEach locus of mtDNA polymorphisms (independent position)Entire loci of mtDNA polymorphisms (succesive positions)
Input (required data)Target (individual cases) and control (normal data)Correct (individual cases) and incorrect (others except correct)
Output (results)Odds ratio or relative riskClusters with predictions
AnalysisCheck odds ratio or relative risk at each positionCheck individuals in clusters based on prediction probabilities

4. Conclusions

This paper examined the relations between Japanese AD patients and their mtSNPs by using the RBF network and a method based on RBF network predictions. As a result, Japanese AD patients were found to be associated with the haplogroups G2a and N9b1. Based on the mtSNPs of the haplogoups, a method for the initial diagnosis of Alzheimer’s disease in Japanese people was proposed. The method can also be used to diagnose of other diseases and identify people likely to live a long time.

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Copyright © 2012 Shigeru Takasaki. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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