Identification of genetic loci associated with pathophysiological changes in Alzheimer's disease progression using neuroimaging genetics
- Author(s)
- 구나세카란 따밀 이니얀
- Issued Date
- 2020
- Abstract
- 알츠하이머병은 복합적인 신경퇴행성 질환으로 치매의 주요 원인 중 하나이다. 알츠하이머병은 뇌에서 베타 아밀로이드 단백질 침착과 신경섬유다발 엉킴과 더불어 특정 뉴런과 시냅스 손실, 신경실 등에 의해 인지능력이 점진적으로 감소되는 특징이 있다. APOE e4는 알츠하이머병의 가장 강력한 유전적 위험인자로 뇌의 베타 아밀로이드 침착과 뇌 위축과 관련이 있으며, APOE 유전자와는 별도로 21개의 유전변이가 알츠하이머병과 연관되어 있다는 보고가 있다. 본 연구는 베타 아밀로이드 침착, 뇌 위축 및 알츠하이머병 진행과 관련된 새로운 유전변이를 발굴하고, 알츠하이머병 진행에서 인종적 차이를 규명하는 연구이다.
본 연구에서는 구조적 자기공명영상에서 측정된 대뇌 피질 두께, 18F-Florbetaben(18F-FBB) 양전자방출 단층촬영영상에서 측정된 베타 아밀로이드 표준섭취계수율, 인지측정값과 유전체 데이터셋을 사용하여 전장유전체 연관성분석을 수행하였다. 첫번째로 자기공명영상 기반 전장유전체 연관성분석 결과, PRDM4 유전자가 대뇌 측두엽의 위축, 알츠하이머병 및 베타 아밀로이드 침착과 연관이 있었음을 확인하였다. 단일염기다형성 기반 연관성 분석 및 haplotype 연관성 분석에서 PRDM4의 rs117303558과 rs73398399는 알츠하이머병과 베타 아밀로이드 침착과 연관이 있었다. 따라서, PRDM4의 rs117303558과 rs73398399는 베타 아밀로이드 침착을 촉진하여 병리학적으로 알츠하이머병과 연관되었음을 시사한다. 18F-FBB 양전자방출 단층촬영영상에서 측정한 뇌의 베타 아밀로이드 침착정도를 전장유전체 연관성 분석한 결과, 19번 염색체(가장 가까운 유전자 CPAMD8)의 rs1297591과 3번 염색체(ARL14)의 rs11345449에 위치한 2개의 새로운 유전변이를 추출하였다. 또한 CPAMD8 유전자에서 missense variant(rs374533)를 검출하였다. 요약하면 뇌의 베타 아밀로이드 병리학에서 중요한 역할을 하는 CPAMD8, ARL14, SMC4, KPNA4, TRIM59, IFT80 유전자를 포함하는 2개의 새로운 유전자(CPAMD8, ARL14)를 추출하였다. 다음으로 다중유전변이 위험점수분석에서 알츠하이머병 초기 및 후기 단계에서 알츠하이머병을 유발하는 베타 아밀로이드, 해마 부피 및 인지영역 등의 알츠하이머병 바이오마커 간 시너지 효과를 확인하였다. 또한 연관성 분석에서 단일염기다형성의 효과 크기 방향이 다중유전변이 위험점수와 알츠하이머병 바이오마커 간 상관관계에 영향을 줄 수 있다는 것을 확인하였다.
본 연구에서는 대규모 분석을 통해 알츠하이머병 환자들의 뇌 병리학적 변화와 연관된 새로운 유전변이를 추출하였다. 더욱이 본 연구는 동아시안 특이 단일염기다형성을 보여주었고 뇌 위축과 대뇌 베타 아밀로이드 침착 및 알츠하어머병과 관련된 유전자를 보여주었으며, 복잡한 신경퇴행성 질환인 치매 원인 및 기전 이해에 중요한 결과이다.|Alzheimer’s disease (AD) is a complex neurodegenerative disorder and considered as one of the main forms of dementia. AD is clinically characterised by progressive deficits in memory, behavioural problems and cognitive impairments. The extracellular deposition of β-amyloid peptides and the intracellular tau hyperphosphorylation are the pathological hallmarks of AD. In particular, the apolipoprotein E (APOE) Ꜫ4 is the most potent genetic risk factor of AD and is associated with both β-amyloid deposition and brain atrophy. Apart from the APOE gene, 21 common genetic variants are found to be associated with AD. The focus was on the identification of comprehensive novel genetic variants associated with brain β-amyloid deposition, atrophy and AD progression. In addition, the role of ethnicity in AD risk at different progressive stages were evaluated. The brain cortical thickness from structural Magnetic Resonance Images (MRI), cerebral β-amyloid standard uptake value ratio (SUVR) from 18F-Florbetaben (18F-FBB) positron emission tomography (PET) images and cognitive measures were applied for genome-wide association study (GWAS) and polygenic analysis. The results of MRI GWA study showed that the PRDM4 gene was associated with brain temporal lobe atrophy, AD risk and cerebral β-amyloid deposition. The results suggested that rs117303558 and rs73398399 SNPs in PRDM4 gene are associated with AD pathology by promoting Aβ deposition in the brain. The 18F-FBB amyloid PET GWAS results showed that there was an association of two novel risk loci with cerebral β-amyloid deposition. Those two novel loci are located at rs12975891 in CPAMD8 gene and rs113454949 in ARL14 gene. A missense variant, rs3745339 was also identified in the CPAMD8 gene. In addition, CPAMD8, ARL14, SMC4, KPNA4, TRIM59 and IFT80 genes were identified to play an important role in β-amyloid pathology in the brain. Next, in a polygenic risk score (PGRS) analysis, it was identified that there was a synergistic effect among AD biomarkers involved in β-amyloid, hippocampal volume and cognitive domain, which drives AD risk in both early and late stages of AD dementia. Additionally, it was also identified that SNPs based on their effect size direction in the association analysis could influence the correlation of AD biomarker with PGRSs of AD. In conclusion, several novel genetic risk loci were identified for the association with AD mediated pathophysiological changes in the brain. Moreover, East Asian specific SNPs were identified to promote AD mediated pathology. Taken together, findings from this study could provide novel insights in understanding this complex neurodegenerative disease.
- Alternative Title
- 알츠하이머병의 뇌손상과 베타아밀로이드 축적에 대한 영상유전학 연구
- Alternative Author(s)
- TAMIL INIYAN GUNASEKARAN
- Department
- 일반대학원 의과학과
- Advisor
- Kun Ho Lee
- Awarded Date
- 2020-08
- Table Of Contents
- I. PART 1: General Introduction 2
II. PART 2: PRDM4 is associated with the Alzheimer’s disease and contributes β-amyloid deposition in the brain 8
Summary 8
II-1. Introduction 10
II-2. Methods 11
II-2-1. Study participants 11
II-2-2. Cognitive assessment and clinical measures 14
II-2-3. SNP genotyping and imputation 14
II-2-4. Magnetic resonance (MR) imaging 15
II-2-5. Positron emission tomography (PET) imaging 15
II-2-6. MRI data processing 16
II-2-7. PET image data processing 17
II-2-8. Statistical analyses 18
II-2-8-1. Association analyses with temporal lobe cortical thickness 18
II-2-8-2. Association analyses on the genetic locus of interest 18
II-2-8-3. Regional SNP based association analysis 19
II-2-8-4. Neuroimaging analysis 21
II-2-8-5. Haplotype based association analysis 21
II-2-8-6. Association analysis on cognitive measures 22
II-3. Results 22
II-3-1. Identification of novel gene associated with brain cortical atrophy in temporal lobe and AD risk 22
II-3-2. PRDM4 rs34156340 associated with brain atrophy in the temporal lobe 44
II-3-3. PRDM4 rs117307558 associated with β-amyloid deposition in the brain temporal lobe 44
II-3-4. Haplotype association analysis on AD risk with SNPs of interest in PRDM4 gene 48
II-3-5. Association of PRDM4 gene SNPs with neuropsychological tests 58
II-4. Discussion 66
III. PART 3: Genome-wide association study on amyloid PET identifies novel risk that regulates cerebral β-amyloid deposition in the East Asians 71
Summary 71
III-1. Introduction 73
III-2. Methods 75
III-2-1. Study participants 75
III-2-2. Florbetaben Positron Emission Tomography (PET) imaging 77
III-2-3. PET image data processing 77
III-2-4. PET image data for replication analyses 78
III-2-5. PET image data processing for replication analysis 78
III-2-6. SNP genotyping and imputation 79
III-2-7. Cognitive assessment and clinical measures 80
III-2-8. H3K27ac ChIP-seq data of entorhinal cortex 80
III-2-9. Statistical analysis 81
III-2-9-1. Genome-wide association analyses 81
III-2-9-2. Gene network-based functional analyses 82
III-2-9-3. Whole-brain β-amyloid deposition analyses 83
III-2-9-4. Replication analysis 83
III-3. Results 87
III-3-1. Novel genome-wide SNPs associated with β-amyloid deposition 87
III-3-2. Genes associated with β-amyloid deposition 107
III-3-3. Gene networks involved in β-amyloid deposition 112
III-3-4. Gene pathways associated with β-amyloid deposition 112
III-3-5. Association of CPAMD8 rs12975891 and ARL14 rs113454949 risk alleles in the whole brain β-amyloid deposition 118
III-3-6. Gender influences the association of CPAMD8 rs12975891 and ARL14 rs113454949 with β-amyloid deposition 122
III-3-7. CPAMD8 rs12975891 and ARL14 rs113454949 mediates β-amyloid deposition in APOE ε4 independent manner 125
III-3-8. AD-associated variation of H3K27ac in the CPAMD8 and ARL14 loci 128
III-3-9. Replication analysis 133
III-4. Discussion 147
IV. PART 4: Multimodal brain imaging and cognitive measures reveal multistage specific multi-polygenic risk for Alzheimer’s disease 155
Summary 155
IV-1. Introduction 157
IV-2. Methods 159
IV-2-1. Study participants 159
IV-2-2. Florbetaben Positron Emission Tomography (PET) imaging 162
IV-2-3. PET image data processing 162
IV-2-4. MRI data processing 163
IV-2-5. Cognitive assessment and clinical measures 163
IV-2-6. Statistical analysis 164
IV-2-7. Estimation of Polygenic Risk Scores (PGRS) 164
IV-3. Results 165
IV-3-1. Correlation of AD biomarkers with PGRSs for AD 165
IV-3-2. Effects of AD biomarker PGRSs in early stage of AD dementia 170
IV-4. Discussion 179
V. PART 5: Overall conclusion 183
VI. ABSTRACT (KOREAN) 185
VII. References 188
- Degree
- Doctor
- Publisher
- 조선대학교 대학원
- Citation
- 구나세카란 따밀 이니얀. (2020). Identification of genetic loci associated with pathophysiological changes in Alzheimer’s disease progression using neuroimaging genetics.
- Type
- Dissertation
- URI
- https://oak.chosun.ac.kr/handle/2020.oak/14254
http://chosun.dcollection.net/common/orgView/200000342026
-
Appears in Collections:
- General Graduate School > 4. Theses(Ph.D)
- Authorize & License
-
- AuthorizeOpen
- Embargo2020-08-28
- Files in This Item:
-
Items in Repository are protected by copyright, with all rights reserved, unless otherwise indicated.