Genome-wide and regional case-control association studies in the genetic analysis of restless legs syndrome [Elektronische Ressource] / Barbara Schormair

Barbara.Schormair

Sujets

• Biologie

Informations

• Publié par: technische_universitat_munchen
• Publié le: 01 janvier 2010
• Nombre de lectures: 22
• Langue: Deutsch
• Poids de l'ouvrage: 3 Mo

Extrait

TECHNISCHE UNIVERSITÄT MÜNCHEN

Lehrstuhl für Entwicklungsgenetik




Genome-wide and Regional Case-Control Association
Studies in the Genetic Analysis of Restless Legs
Syndrome


Barbara Schormair



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. H.-R. Fries
Prüfer der Dissertation:
1. Univ.-Prof. Dr. W. Wurst
2. apl. Prof. Dr. J. Winkelmann
3. Univ.-Prof. Dr. Th. A. Meitinger


Die Dissertation wurde am 07.10.2009 bei der Technischen Universität München eingereicht und
durch die Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt am
30.04.2010 angenommen.







































Genome-wide and Regional Case-Control Association
Studies in the Genetic Analysis of Restless Legs
Syndrome




Kumulative Arbeit



Barbara Schormair
































Für meine Eltern

TABLE OF CONTENTS
Table of contents
Table of contents ......................................................................................................................... I 
Abbreviations ........................................................................................................................... III 
Summary ................................................................................................................................... V 
Zusammenfassung ................................................................................................................... VII 
1  Introduction ........................................................................................................................ 1 
1.1  Association studies in the genetic mapping of common diseases .............................. 1 
1.1.1  Rationale and basic principles ............................................................................ 1 
1.1.2  Relevance of linkage disequilibrium to study design and analysis .................... 3 
1.1.3  Study power and detection range ....................................................................... 5 
1.1.4  Minimizing false-positive and false-negative associations ................................ 6 
1.2  Restless legs syndrome (RLS): a common complex disease ..................................... 9 
1.2.1  Clinical characteristics and epidemiology .......................................................... 9 
1.2.2  Classification and endophenotypes .................................................................. 11 
1.2.2.1  Idiopathic (primary) and symptomatic (secondary) RLS ............................. 11 
1.2.2.2  Familial (early-onset) and sporadic (late-onset) endophenotypes ................ 12 
1.2.3  Pathophysiology ............................................................................................... 13 
1.2.4  Genetic epidemiology ...................................................................................... 15 
1.3  Aims of this thesis .................................................................................................... 17 
2  Results and Discussion ..................................................................................................... 18 
2.1  Idiopathic RLS ......................................................................................................... 18 
2.1.1  Association of variants in NOS1 (nNOS) on chromosome 12 (RLS-1) ........... 18 
2.1.1.1  Study rationale and design ........................................................................... 18 
2.1.1.2  Association analysis results and finemapping of NOS1 ............................... 19 
2.1.1.3  Discussion .................................................................................................... 20 
2.1.2  Association of variants in MEIS1, BTBD9, and MAP2K5/LBXCOR1 – results
from a genome-wide association study ............................................................ 24 
2.1.2.1  Study rationale and design 24 
2.1.2.2  Association results of the genome-wide exploratory stage .......................... 24 
2.1.2.3  Replication, finemapping, and haplotype analysis ....................................... 25 
2.1.2.4 28 
2.1.3  Association of variants in PTPRD on chromosome 9 (RLS-3) ....................... 31 
2.1.3.1  Study rationale and design ........................................................................... 31 
ITABLE OF CONTENTS
2.1.3.2  Association results of the exploratory phase ................................................ 31 
2.1.3.3  Replication of association signals within PTPRD and mutation screening of
PTPRD ......................................................................................................... 32 
2.1.3.4  Discussion .................................................................................................... 34 
2.2  Symptomatic RLS .................................................................................................... 36 
2.2.1  Association study of MEIS1, BTBD9, MAP2K5/LBXCOR1, and PTPRD in
uremic RLS ....................................................................................................... 36 
2.2.1.1  Study rationale and design ........................................................................... 36 
2.2.1.2  Association results ........................................................................................ 36 
2.2.1.3  Discussion .................................................................................................... 37 
3  Conclusions and future developments .............................................................................. 39 
4  Bibliography ..................................................................................................................... 44 
5  Appendices ....................................................................................................................... 57 
Published and submitted manuscripts and personal contributions to them:
1 Published manuscript 1: Variants in the neuronal nitric oxide synthase
(nNOS, NOS1) gene are associated with restless legs syndrome.
2 Published manuscript 2: Genome-wide association study of restless legs
syndrome identifies common variants in three genomic regions.
3 Published manuscript 3: PTPRD (protein tyrosine phosphatase receptor type
delta) is associated with restless legs syndrome.
4 Submitted manuscript 1: Variants in MEIS1 and BTBD9 are associated with
restless legs syndrome in end-stage renal disease.
Danksagung
Conferences and Presentations
Publications
IIABBREVIATIONS
Abbreviations
ARF attributable risk fraction
AUC area under the curve
B Bonferroni
bp base pair
BTBD9 BTB (POZ) domain containing 9
CDCV common disease common variant
chr chromosome
CNV copy number variation
CI confidence interval
CNS central nervous system
CSF cerebrospinal fluid
DNA deoxyribonucleic acid
DZ dizygotic
ESRD end-stage renal disease
GRR genotypic relative risk
GWAS genome-wide association study
HWE Hardy-Weinberg equilibrium
iRLS idiopathic RLS
IRLSSG International Restless Legs Syndrome Study Group
kb kilobase
LBX1 ladybird homeobox 1
LBXCOR1 Lbxcor1 homolog (mouse)
LD linkage disequilibrium
L-DOPA levodopa
MAF minor allele frequency
Mb megabase
MEIS1 Meis homeobox 1
MRI magnetic resonance imaging
MZ monozygotic
NO nitric oxide
NOS1, nNOS neuronal nitric oxide synthase
OR odds ratio
P P value
PLM periodic limb movements
PLMW periodic limb movements while awake
PLMS ovements in sleep
PTPRD protein tyrosine phosphatase receptor type delta
RNA ribonucleic acid
RLS restless legs syndrome
ROC receiver operating characteristic
SNP single nucleotide polymorphism
sRLS symptomatic RLS
TH tyrosine hydroxylase
uRLS uremic
VNTR variable number of tandem repeats

III
IV