To identify the risk factors being associated with aetiology of amyotrophic lateral sclerosis (ALS), a series of systematic reviews based on existing observational epidemiological studies identified through searching of bibliographic databases were conducted. Associations between ALS and a number of genetic and environmental risk factors were examined using meta-analysis. Specifically we found that previous exposure to lead, pesticides, solvents, experience of trauma and electric shock were associated with relative increased risks of developing ALS of 86% [odds ratio (OR) =1.86, 95% CI: 1.39-2.48], 57% (OR=1.57,95% CI: 1.19-2.08), 47% (OR=1.47, 95%CI: 1.13-1.80), 64% (OR=1.64; 95%CI: 1.36-1.98), and 2.27% (OR=3.27, 95%CI:1.87-5.73) respectively, compared to their corresponding controls. The presence of intermediate CAG repeat expansion in the ATXN2 gene was associated with a 4.4 -fold increase in the risk of ALS (OR=4.44, 95%CI: 2.91-6.76). However, the attributable risk associated with each identified risk factor was estimated to be less than 5% of all ALS cases. These results confirm that ALS is a rare multifactorial degenerative condition of motor-neurons.

La préférence homosexuelle masculine (PHM) est considérée comme un paradoxe darwinien car c'est un trait partiellement héritable, induisant une baisse de succès reproducteur, ayant une fréquence (en Occident) entre 2 et 6 % et qui semble propre à l'espèce humaine (en excluant les espèces domestiquées). La sélection de parentèle, ou bien un facteur pléiotrope antagoniste sont classiquement proposés, bien que l'essentiel des données proviennent de sociétés occidentales. Nous avons proposé une nouvelle hypothèse, basée sur la stratification sociale et permettant d'expliquer la spécificité humaine, dans laquelle la migration sexe-dépendante de type hypergyne amplifie la sélection d'un gène antagoniste. La plausibilité de cette hypothèse est confirmée par des modèles théoriques d'ESS et des modélisations individu-centrés. De plus, une analyse comparative basée sur données anthropologiques a permis de montrer un lien entre le niveau de stratification d'une société et la probabilité que la PHM soit connue dans cette société. La sélection de parentèle, mesurée dans une société non-occidentale (Indonésie), semble participer à la compensation du coût reproductif de la PHM, mais insuffisamment pour en expliquer le maintien. Les principales caractéristiques familiales associées à la PHM, l'excès de grands frères, et la fécondité accrue dans certaines classe d'apparentés, se retrouvent également en Indonésie. Toutefois, en Indonésie, les classes d'apparentés concernées différent en partie des résultats obtenus en occident et ne correspondent pas aux attendues de l'hypothèse de sélection sexuellement antagoniste portée par le chromosome X. La prise en compte de l'interaction entre facteurs sociaux et biologiques ainsi que l'acquisition de données hors des sociétés occidentales ouvrent de nouvelles perspectives de compréhension de ce paradoxe darwinien. / Male homosexual preference (MHP) is considered as a Darwinian paradox, as it is partially heritable, induces a reproductive cost, has a prevalence estimated (in western countries) between 2 and 6%, and seems to be specific to humans (excluding domesticated species). Kin selection or sexually antagonistic factors have been proposed as possible explanations, although most data come from western countries. Here, we proposed a new hypothesis, based on social stratification, able to explain the specificity of human MHP, in which hypergyny (up-migration of the women) enhances the selection of a sexually antagonistic gene. This hypothesis is supported by theoretical models (ESS) and individual-based modelling. Furthermore, a comparative analysis based on anthropological data showed that the level of social stratification predicts the probability for MHP to be known in a society. Kin selection was tested in a non-western society (Indonesia), and seems to contribute to the compensation of the reproductive costs associated with MHP, although this effect alone was insufficient to explain the maintenance of MHP. The main biodemographic features associated with MHP, an excess of older brother and an increased fecundity of some classes of relatives, were also found in Indonesia. However, the classes of relatives affected by this increased fecundity differ from the classes affected in western populations, and differ from the predictions of the sexually antagonistic genetic factor hypothesis displayed on an X chromosome. Taking into account the interaction between social and biological factors, together with the acquisition of new data in non-western populations, open new perspectives in our understanding of this Darwinian paradox.

To identify the risk factors being associated with aetiology of amyotrophic lateral sclerosis (ALS), a series of systematic reviews based on existing observational epidemiological studies identified through searching of bibliographic databases were conducted. Associations between ALS and a number of genetic and environmental risk factors were examined using meta-analysis. Specifically we found that previous exposure to lead, pesticides, solvents, experience of trauma and electric shock were associated with relative increased risks of developing ALS of 86% [odds ratio (OR) =1.86, 95% CI: 1.39-2.48], 57% (OR=1.57,95% CI: 1.19-2.08), 47% (OR=1.47, 95%CI: 1.13-1.80), 64% (OR=1.64; 95%CI: 1.36-1.98), and 2.27% (OR=3.27, 95%CI:1.87-5.73) respectively, compared to their corresponding controls. The presence of intermediate CAG repeat expansion in the ATXN2 gene was associated with a 4.4 -fold increase in the risk of ALS (OR=4.44, 95%CI: 2.91-6.76). However, the attributable risk associated with each identified risk factor was estimated to be less than 5% of all ALS cases. These results confirm that ALS is a rare multifactorial degenerative condition of motor-neurons.

Background: Genome-wide association studies (GWAs) have identified almost one hundred genetic loci associated with variances in human blood lipid phenotypes including very low-density lipoprotein cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol and triglycerides. Nevertheless the revealed loci only explain a small fraction of heritability and therefore a subtile phenotype of cholesterol homoestasis was examined in our study for the very first time. Methods and Results: Using a multi-stage approach of a GWA, firstly, a genome-wide analysis (Affymetrix 500K GeneChip) for serum lanosterol and serum total cholesterol using LC-MS/MS was conducted in 1495 participants of the KORA-S3/F3 cohort with subsequent replication in two additional independent samples of the the KORA-S3/F3 cohort (n = 1157) and CARLA cohort (n = 1760). Two genetic variants, SNP rs7703051 and rs17562686, in the HMGCR locus were significantly associated with serum lanosterol and showed similar effects of elevated serum lanosterol for each minor allele (combined n = 4412: p = 1,4 x 10-10, +7,1% and p = 4,3 x 10-6, +7,8%). Furthermore, rs7703051 showed a nominal statistical significance to serum cholesterol (p = 0,04). A combined analysis of both SNPs demonstrated that observed associations of rs17562686 can be partly explained by LD with rs7703051 being the primary polymorphism in that study. Nevertheless, rs17562686 shows consistent independent effects on serum lanosterol, thus being associated to a lipid phenotype for the very first time. The following SNP-fine mapping of the HMGCR locus was carried out in the CARLA cohort with subsequent validation in the LE-Heart cohort (n = 1895). The recently published SNP rs3846662 being in tight LD with rs7703051 could be associated with variances of serum lanosterol in both cohorts and functional in vivo studies of gen expression using qRT-PCR assays demonstrated a highly significant association of higher expression of alternatively spliced HMGCR mRNA lacking exon 13 with homozygosity for the rs3846662 major allele in 51 human liver samples (p < 0,01) and 958 human PBMCs (p = 2,1 x 10-7). The overall HMGCR gen expression was not affected. Further investigation of in vivo HMG-CoA reductase enzyme activity in both human samples (n = 48 and n = 55) using anionic exchange column chromatography and scintillation counting of [3-14C]-HMG-CoA and [5-3H]-mevalonolacton did not show any significant results. In addition there was not any association in the LE-Heart cohort between these SNPs and the development of CAD. Finally, rs7703051 could be replicated for already published total cholesterol (combined n = 4412) and rs3846662 for LDL-cholesterol (LE-Heart n = 1895). Since fine mapping in CARLA showed several SNPs throughout the HMGCR locus being in LD with rs17562686 we performed a DNA sequencing of the extended 5´-HMGCR promotor region in six human liver samples. A unknown SNP was discovered in the promotor but could not be associated with any of the examined phenotypes mentioned above. The minor allele of SNP rs5909 situated next to the stop codon and being in high LD with rs17562686 was associated with elevated serum lanosterol and slightly reduced HMGCR gen expression, but further studies including the above mentioned as well as measurement of 3’-UTR transcript lengths using qRT-PCR assays did not produce significant results. Conclusion: The phenotype serum lanosterol could be associated with genetic polymorphisms (e.g. rs7703051) in the HMGCR locus. Therefore already published associations of HMGCR with total cholesterol and LDL-cholesterol can be explained by variances of cholesterol homeostasis. The SNP rs17562686 could be associated with a phenotype of human blood lipids for the very first time. Subsequent gen expression analyses demonstrated a highly significant association of rs3846662 with variant patterns of HMGCR alternative splicing. A significant effect of alternatively spliced protein on enzyme activity and a association of these SNPs with CAD could not be shown.

Background: Genome-wide association studies (GWAs) have identified almost one hundred genetic loci associated with variances in human blood lipid phenotypes including very low-density lipoprotein cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol and triglycerides. Nevertheless the revealed loci only explain a small fraction of heritability and therefore a subtile phenotype of cholesterol homoestasis was examined in our study for the very first time. Methods and Results: Using a multi-stage approach of a GWA, firstly, a genome-wide analysis (Affymetrix 500K GeneChip) for serum lanosterol and serum total cholesterol using LC-MS/MS was conducted in 1495 participants of the KORA-S3/F3 cohort with subsequent replication in two additional independent samples of the the KORA-S3/F3 cohort (n = 1157) and CARLA cohort (n = 1760). Two genetic variants, SNP rs7703051 and rs17562686, in the HMGCR locus were significantly associated with serum lanosterol and showed similar effects of elevated serum lanosterol for each minor allele (combined n = 4412: p = 1,4 x 10-10, +7,1% and p = 4,3 x 10-6, +7,8%). Furthermore, rs7703051 showed a nominal statistical significance to serum cholesterol (p = 0,04). A combined analysis of both SNPs demonstrated that observed associations of rs17562686 can be partly explained by LD with rs7703051 being the primary polymorphism in that study. Nevertheless, rs17562686 shows consistent independent effects on serum lanosterol, thus being associated to a lipid phenotype for the very first time. The following SNP-fine mapping of the HMGCR locus was carried out in the CARLA cohort with subsequent validation in the LE-Heart cohort (n = 1895). The recently published SNP rs3846662 being in tight LD with rs7703051 could be associated with variances of serum lanosterol in both cohorts and functional in vivo studies of gen expression using qRT-PCR assays demonstrated a highly significant association of higher expression of alternatively spliced HMGCR mRNA lacking exon 13 with homozygosity for the rs3846662 major allele in 51 human liver samples (p < 0,01) and 958 human PBMCs (p = 2,1 x 10-7). The overall HMGCR gen expression was not affected. Further investigation of in vivo HMG-CoA reductase enzyme activity in both human samples (n = 48 and n = 55) using anionic exchange column chromatography and scintillation counting of [3-14C]-HMG-CoA and [5-3H]-mevalonolacton did not show any significant results. In addition there was not any association in the LE-Heart cohort between these SNPs and the development of CAD. Finally, rs7703051 could be replicated for already published total cholesterol (combined n = 4412) and rs3846662 for LDL-cholesterol (LE-Heart n = 1895). Since fine mapping in CARLA showed several SNPs throughout the HMGCR locus being in LD with rs17562686 we performed a DNA sequencing of the extended 5´-HMGCR promotor region in six human liver samples. A unknown SNP was discovered in the promotor but could not be associated with any of the examined phenotypes mentioned above. The minor allele of SNP rs5909 situated next to the stop codon and being in high LD with rs17562686 was associated with elevated serum lanosterol and slightly reduced HMGCR gen expression, but further studies including the above mentioned as well as measurement of 3’-UTR transcript lengths using qRT-PCR assays did not produce significant results. Conclusion: The phenotype serum lanosterol could be associated with genetic polymorphisms (e.g. rs7703051) in the HMGCR locus. Therefore already published associations of HMGCR with total cholesterol and LDL-cholesterol can be explained by variances of cholesterol homeostasis. The SNP rs17562686 could be associated with a phenotype of human blood lipids for the very first time. Subsequent gen expression analyses demonstrated a highly significant association of rs3846662 with variant patterns of HMGCR alternative splicing. A significant effect of alternatively spliced protein on enzyme activity and a association of these SNPs with CAD could not be shown.

Human complex diseases, like Diabetes and Cancer, affect many people worldwide today. Despite existing knowledge, many of these diseases are still not preventable. Complex diseases are known to be caused by a combination of genetic factors, as well as environmental and life style factors. The scope of this investigation covered the genomics of Type 1 Diabetes (T1D). There are 49 human genomic regions that are known to carry markers (disease-associated single nucleotide mutations) for T1D, and these were extensively studied in this research. The aim was to find out in how far this disease may be caused by problems in gene regulation rather than in gene coding. For this, the genetic factors associated with T1D, including the single point mutations and susceptibility regions, were characterised on the basis of their genomic attributes. Furthermore, mutations that occur in binding sites for transcription factors were analysed for change in the conspicuousness of their binding region, caused by allele substitution. This is called SNP (Single nucleotide polymorphism) sensitivity. From this study, it was found that the markers for T1D are mostly non-coding SNPs that occur in introns and non-coding gene transcripts, these are structures known to be involved in gene regulatory activity. It was also discovered that the T1D susceptibility regions contain an abundance of intronic, non-coding transcript and regulatory nucleotides, and that they can be split into three distinct groups on the basis of their structural and functional genomic contents. Finally, using an algorithm designed for this study, thirty-seven SNPs that change the representation of their surrounding region were identified. These regulatory mutations are non-associated T1D-SNPs that are mostly characterised by Cytosine to Thymine (C-T) transition mutations. They were found to be closer in average distance to the disease-associated SNPs than other SNPs in binding sites, and also to occur frequently in the binding motifs for the USF (Upstream stimulatory factor) protein family which is linked to problems in Type 2 diabetes.