A candidate gene and a genome-wide association study in depression [Elektronische Ressource] : I. a candidate gene study reveals variants in NTRK2 conferring risk to mood disorder patients for a life history of attempted suicide; II. a genome-wide study identifies SLC6A15 as a novel susceptibility gene for major depression / Martin A. Kohli

Kohlim

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• Gesundheit

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• Publié par: technische_universitat_munchen
• Publié le: 01 janvier 2009
• Nombre de lectures: 64
• Langue: Deutsch
• Poids de l'ouvrage: 3 Mo

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TECHNISCHE UNIVERSITÄT MÜNCHEN
Lehrstuhl für Entwicklungsgenetik




A Candidate Gene and a Genome-wide Association Study in Depression
I A Candidate Gene Study Reveals Variants in NTRK2 Conferring Risk to
Mood Disorder Patients for a Life History of Attempted Suicide
II A Genome-Wide Study Identifies SLC6A15 as a Novel Susceptibility Gene
for Major Depression



Martin A. Kohli



Vollständiger Abdruck der von der Fakultät Wissenschaftszentrum Weihenstephan für
Ernährung, Landnutzung und Umwelt der Technischen Universität München zur Erlangung
des akademischen Grades eines
Doktors der Naturwissenschaften
genehmigten Dissertation.

Vorsitzender: Univ.-Prof. Dr. E. Grill
Prüfer der Dissertation:
1. Univ.-Prof. Dr. W. Wurst
2. Univ.-Prof. Dr. Chr.-C. Schön


Die Dissertation wurde am 04.08.2008 an der Technischen Universität München eingereicht
und durch die Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung
und Umwelt am 19.03.2009 angenommen.

CONTENTS
ABSTRACT ............................................................................................................................. 1
ZUSAMMENFASSUNG ........................................................................................................... 3
1 INTRODUCTION................................................................................................................ 6
1.1 Human Genetic Association in Complex Disease ............................................ 6
1.1.1 Overview................................................................................................... 6
1.1.2 Major factors influencing genetic association analysis............................... 8
1.1.2.1 Linkage disequilibrium ........................................................................ 8
1.1.2.2 The International HapMap project – tagging SNPs became available ...
......................................................................................................... 10
1.1.2.3 The effect size .................................................................................. 11
1.1.2.4 Multiple testing.................................................................................. 13
1.1.2.5 Disease and marker allele frequencies ............................................. 15
1.1.2.6 Misclassification Errors ..................................................................... 16
1.1.2.7 Deviation from Hardy-Weinberg equilibrium (DHW) .......................... 17
1.1.2.8 Population stratification..................................................................... 18
1.1.3 Power calculation in association studies.................................................. 19
1.2 Genetics of Mood Disorders .......................................................................... 21
1.2.1 Clinical Features and Epidemiology of MDD ........................................... 21
1.2.2 Genetic Epidemiology of MDD ................................................................ 22
1.2.3 Molecular Genetic Studies in MDD.......................................................... 23
1.2.4 Epidemiology of suicidal behavior ........................................................... 24
1.2.5 Genetic bases of suicidal behavior.......................................................... 25
1.2.6 Molecular Genetic Studies of suicidal behavior ....................................... 25
1.2.7 The neurotrophin hypothesis of MDD and suicidal behavior.................... 26
1.2.8 Genetic association studies on neurotrophins in mood dis-orders........... 29
1.3 Study Design of this Dissertation ................................................................... 30
1.3.1 The hypothesis-driven candidate gene association approach.................. 30
1.3.2 The hypothesis-free genome-wide association approach........................ 31



i 2 MATERIALS AND METHODS ......................................................................................... 33
2.1 Human Genetic Association Studies.............................................................. 33
2.1.1 Recruitment and sample characterization................................................ 33
2.1.1.1 Discovery sample.............................................................................. 33
2.1.1.2 Replication sample............................................................................ 35
2.1.1.3 Epidemiological sample .................................................................... 37
2.1.2 DNA preparation...................................................................................... 38
2.1.3 SNP selection and genotyping................................................................. 38
2.1.4 Statistics.................................................................................................. 40
2.1.4.1 Power calculation.............................................................................. 40
2.1.4.2 Genomic controls.............................................................................. 40
2.1.4.3 Association testing............................................................................ 41
2.1.4.4 Linkage disequlibrium ....................................................................... 43
2.2 SNP-genotype functional correlation analyzes............................................... 43
2.2.1 Genotype-dependent human mRNA levels.............................................. 43
2.2.2 Imaging genomics ................................................................................... 45
12.2.2.1 Nuclear magnetic resonance spectroscopy ( H-NMR) ...................... 45
2.2.2.2 Regional volumetry ........................................................................... 48
2.3 A mouse model on chronic stress.................................................................. 50
2.3.1.1 Animal housing ................................................................................. 50
2.3.1.2 Chronic stress paradigm ................................................................... 50
2.3.1.3 Behavioral analysis........................................................................... 51
2.3.1.4 Tissue dissection and expression profiling ........................................ 51
2.3.1.5 Gene expression analysis in stress vulnerable versus ..........................
stress resistant mice ......................................................................... 53

3 RESULTS......................................................................................................................... 54
3.1 Results of the candidate gene association study on MDD and ..........................
a life history of attempted suicide................................................................... 54
3.1.1 Quality control and SNP marker coverage............................................... 54
3.1.2 Genetic associations in the discovery sample ......................................... 55
3.1.2.1 Case-control association with MDD................................................... 55
3.1.2.2 Associations with SA among patients................................................ 55
3.1.3 Replication of associations with SA......................................................... 56
3.1.4 Interdependency of the associated SNPs and their location in NTRK2.... 56
ii 3.1.5 Association with SA in the combined sample .......................................... 58
3.1.5.1 Single SNP associations................................................................... 58
3.1.5.2 Multilocus model and SNP-SNP interaction ...................................... 60
3.2 Results of the Genome-wide Association Study in MDD................................ 62
3.2.1 Quality control and population stratification in the discovery sample ....... 62
3.2.2 Association results from the GWAS in MDD............................................ 63
3.2.3 LD structure among the associated SNPs on 12q21.31 .......................... 64
3.2.4 Association results in the replication and combined sample .................... 65
3.2.5 Nominal DHW in controls of the discovery sample .................................. 67
3.2.6 The number of risk-allele carriers is correlated............................................
with the expected risk for MDD............................................................... 68
3.2.7 Rs1545843 associations with demographic and .........................................
illness-related variables........................................................................... 70
3.2.8 Genomic context of the associated region on 12q21.31 .......................... 71
3.3 Genotype-related functional correlates with SNPs from the GWAS ............... 73
3.3.1 Risk allele carriers display lower SLC6A15 mRNA levels........................ 73
3.3.2 Healthy risk allele carriers display lower hippocampal.................................
N-acetylaspartate and glutamine/glutamate levels .................................. 76
3.3.3 Genetic associations with volumetric measures ..........................................
of the hippocampal complex.........................................................