2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
4,8% and 9,7%, relatively, p=0,025) of S19W of ApoA5 gene polymorphism
between children with risk factors of CAD and control group . We
haven’t significant differences in genotypes and alleles distribution of
A-1131T>C of ApoA5 gene polymorphism in boys, girls and total group
between children with risk factors of CAD and control group .conclusion:
children with risk factors of metabolic syndrome had more frequent
SS genotype and S allele S19W of ApoA5 gene polymorphism
than in healthy children .
P06.113
Influence of TNF (G-308A) polymorphism on level of a tNF-alpha
in blood at chronic diseases of lungs and liver
I. A. Goncharova1 , G. N. Seitova2 , E. V. Beloborodova2 , O. P. Bukreeva2 , I. L.
Purlik2 , V. P. Puzyrev1 ;
1Scientific Research Institute of Medical Genetics, Tomsk, Russian Federation,
2Siberian State Medical University, Tomsk, Russian Federation.
Polymorphism in TNF (G-308A) gene was studied for association with
tumor necrosis factor alpha level in blood of patients with chronic viral
hepatitis (n=60) and chronic obstructive pulmonary disease (COPD)
(n=72) . The patients were from Tomsk population . It has been shown
that level of TNF-alpha in patients with chronic viral hepatitis depends
on TNF (G-308A) genotype: GG - 137 .9±222 .49; AG - 48 .7±58 .16;
AA -31.0±1.41 (p=0.018). The finding suggests that in patients with
chronic viral hepatitis allele A is associated with smaller intensity of
an inflammation and fibrosis in a liver. In the patients with COPD, carriers
of genotype AG had lower level TNF-alpha in blood at exacerbation
(60,1±20,68) and during remission (75,1±16,56) in comparison
with carriers of a genotype GG (193,8±50,65; 370,3±109,4) (p=0,041;
p=0,026) . Genotype AA has not been revealed . Thus, at patients with
COPD allele A is associated with low level TNF-alpha in blood, like in
patients with chronic viral hepatitis . These results are discordant with
known data on association of allele A with increased level of production
of TNF-alpha . There might be several explanations of the discrepancy,
including population specificity of genetic predisposition to various
diseases and different LD structure in adjacent regions of genome
(including 3’-UTR region of the gene) in different populations, as well
as different environmental factors that can influence realization of a
“genetic background” .
P06.114
somatic genome structural variations
V. Sgaramella, J. L. Williams, F. Salamini;
CERSA, Lodi, Italy.
The notion that cells of common ancestry harbour genomes different
from each other is strengthening . The differences may be either scheduled
(e . g ., immune response), or unscheduled (e .g ., damage effects),
and alter DNA structures . Simple repeats, interspersed sequences,
(retro)transposons, pseudogenes, transgenes, etc, may assume unusual
non-B conformations, affecting recognition by DNA-metabolizing
enzymes . This may trigger a crescendo of variations, from base substitutions
to aneuploidy. Epigenetics modifies chromatin and modulates
transcription in somatic cells, but can be erased in germ cells . The
resulting RNA may activate novel priming and retrotranscription thus
concurring to genome rearrangements, competent to drive evolution
and contribute to development . The resulting somatic genome structural
variations (SGSV) may accelerate cell duplication and favour
clonal amplification, occasionally optimizing some functions, but often
deranging growth . Consequently, multicellular organisms are bound to
be eventually genomic mosaic .
We report on: 1. the amplification of the genome of as few cells as
possible of diverse somatic tissues, as a prerequisite for detecting
SGSV; 2. their identification and characterization. For step 1, we have
developed a modified isothermal whole genome strand displacement
amplification based on the circularization of restricted genomes. For
step 2, we are investigating two approaches, based on AFLP and differential
2D-gel electrophoresis; others are being considered such as
mass sequencing and comparative genome hybridization. Benefits are
expected in basic sciences (soma-germline-environment crosstalk,
mechanisms of gene copy and chromosome number variations, evodevo),
as well as applications (diagnosis, therapy, stem cells, transgenetics,
cloning, plant and livestock breeding) .
P06.115
Cross-validation filtering for genome-wide association scan
Z. Vitezica1,2 , M. Martinez1,3 ;
1 2 INSERM U563, Toulouse, France, Université Paul Sabatier III, Toulouse,
France, 3Université Paul Sabatier III, Toulouse, France.
Genome-wide association studies (GWAS) with hundreds of thousands
of markers are now feasible . In a one-stage study design, stringent
significance thresholds are used because of the multiple-test problem.
Hence, GWAs have low power to detect uncommon disease genes
with low effects, even in relatively large datasets (several thousands
of cases and controls) . Alternative approaches have been proposed
(Satagopan et al., 2002; Skol et al., 2005). Briefly, the full set of markers
is tested in a fraction of the dataset only . A set of “best” markers,
to be followed-up in either an independent (two-stages design) or an
increased (joint-analysis design) sample, is identified from pointwise
P-values. Yet, relaxing the significance thresholds may not compensate
decrease in power due to the sample size reduction in stage-1 .
Here, we propose to use the consistency in the “associated” allele as a
new criterion to select the “best” markers . The Consistency Rate (CR)
is the number of times that allele 1 is found to be the risk allele out of
n sub-samples . Each marker is ranked according to its CR value . Nondisease
markers are expected to have CR values of 50% . Thus, in our
approach, the “best” markers are those with CR values significantly
different from 50%. We study the statistical properties of our filtering
approach by simulations, using a panel of 30,000 SNPs from HapMap
data, and under different conditions (disease gene effects; sample sizes;
number of sub-samples n) . We report type I error and power rates
of our filtering and of other approaches.
P06.116
Identification of novel susceptibility loci 7q31 and 9p13 for
bipolar disorder in an isolated population
O. M. Palo 1 , P. Soronen 1 , K. Silander 1 , T. Varilo 1 , K. Tuononen 1 , M. Perola 1 , T.
Kieseppä 2 , T. Partonen 2 , J. Lönnqvist 2,3 , T. Paunio 1,4 , L. Peltonen 1,5 ;
1 FIMM, Institute for Molecular Medicine Finland and National Public Health Institute,
Helsinki, Finland, 2 Department of Mental Health and Alcohol Research,
National Public Health Institute, Helsinki, Finland, 3 Department of Psychiatry,
Helsinki University Central Hospital, Helsinki, Finland, 4 University of Helsinki
and Helsinki University Central Hospital, Department of Psychiatry,, Helsinki,
Finland, 5 Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
We performed a linkage analysis on 23 Finnish families with bipolar
disorder and originating from the North-Eastern region of Finland, by
using the Illumina Linkage Panel IV (6K) Array . The Panel IV had an
average intermarker spacing of 0 .64 cM across the entire genome .
One phenotypic model, broad mood disorder including bipolar I disorder
and recurrent depressive disorder, was used in the analyses . We
found genome-wide significant evidence of linkage to chromosomes
7q31 (LOD = 3 .20) and 9p13 .1 (LOD = 4 .02) . Analyzing the best markers
on the full set of 179 Finnish bipolar families supported the findings
on chromosome 9p13 (maximum LOD score of 3 .02 at position 383
Mb immediately upstream of the centromere . This region harbors several
interesting candidate genes, including contactin associated protein-like
3 (CNTNAP3) and aldehyde dehydrogenase 1 (ALDH1B1) .
For the 7q31 locus, only one extended pedigree and seven families
originating from the same late settlement region of Finland provided
evidence of linkage, suggesting that a gene predisposing to bipolar
disorder is enriched in that region of Finland . The loci on the centromeric
region of 9p13 and telomeric region of 7q31 may represent novel
susceptibility loci for mood disorder in the Finnish population .
P06.117
mapping of a locus for Geroderma Osteodysplasticum to
chromosome 1q23-q25
F. Brancati 1,2 , V. Fodale 3 , G. Zampino 4 , M. Tartaglia 3 , B. Dallapiccola 1,5 ;
1 IRCCS CSS Mendel Institute, Rome, Italy, 2 Ce.S.I. e Dipartimento di Scienze
Biomediche, Fondazione G. d’Annunzio, Chieti, Italy, 3 Dipartimento di Biologia
Cellulare e Neuroscienze, Istituto Superiore di Sanità, Rome, Italy, 4 Istituto di
Clinica Pediatrica, Università Cattolica del Sacro Cuore, Rome, Italy, 5 Dipartimento
di Medicina Sperimentale, Università La Sapienza, Rome, Italy.
Geroderma Osteodisplasticum (GO; OMIM%231070) is a rare autosomal
recessive condition described so far in less than 30 patients
whose molecular defect is still unknown . GO is characterized by pre-