Family, twin, and adoption studies have indicated that genetic and environmental factors contribute to the development of alcohol dependence (AD). We conducted a low-density genome-wide association analysis to identify genetic variants influencing AD. We used 11,120 SNPs from the Affymetrix 10K Genechips genotyped in 116 Caucasian pedigrees (272 nuclear families) from Genetic Analysis Workshop 14, a subset from the Collaborative Study on the Genetics of Alcoholism (COGA). Family-based association analyses for AD were performed by the PBAT program for autosomal SNPs and by the FBAT program for X-chromosome SNPs. We identified 37 SNPs associated with AD (P < 10 -3), thirteen of which were located in known genes. The most significant association with AD was observed with SNP rs1986644 (P = 8.51 × 10 -6) at 13q22 near EDNRB gene. The next best signal was at 1q41 in USH2A (rs532342, P = 1.07 × 10 -5) and the third region was at 3q25.31 in TIPARP (rs1367311, P = 2.31 × 10 -5). Furthermore, we found support for association of MAOA gene (P = 4.14 × 10 -4 for rs979606). Six of the 37 AD associated SNPs were confirmed to be associated with AD in Australian twin-family study sample (P < 0.05). Interestingly, four SNPs in DSCAML1 at 11q23 reached the genome-wide significance (the top SNP is rs10892169 with P = 5.31 × 10 -9), while rs637547 in NKAIN2 at 6q21 showed strong association with AD (P = 5.11 × 10 -7) in the replication sample. These findings offer the potential for new insights into the pathogenesis of AD and will serve as a resource for replication in other populations to elucidate the potential role of these genetic variants in AD.

Family, twin, and adoption studies have indicated that human intelligence quotient (IQ) has significant genetic components. We performed a low-density genome-wide association analysis with a family-based association test to identify genetic variants influencing IQ, as measured by Wechsler Adult Intelligence Scale full-score IQ (FSIQ). We examined 11,120 single-nucleotide polymorphisms (SNPs) from the Affymetrix GeneChips 10K mapping array genotyped in 292 nuclear families from Genetic Analysis Workshop 14, a subset from the Collaborative Study on the Genetics of Alcoholism (COGA). A replication analysis was performed using part of International Multi-Center ADHD Genetics Project (IMAGE) dataset. Twenty-two SNPs were identified as having suggestive associations with IQ (p<10-3) in the COGA sample and eleven of the SNPs were located within known genes. In particular, NTM at 11q25 (rs411280, p=0.000764) and NR3C2 at 4q31.1 (rs3846329, p=0.000675) were two novel genes which have not been associated with IQ in other studies. It has been reported that NTM might play a role in late-onset Alzheimer disease while NR3C2 may be associated with cognitive function and major depression. The associations of these two genes were well-replicated by single-marker and haplotype analyses in the IMAGE sample. In conclusion, our findings provide evidence that chromosome regions of 11q25 and 4q31.1 contain genes affecting IQ. This study will serve as a resource for replication in other populations.

No description available.

<p>The breakdown of self-tolerance is the main driving force behind susceptibility to SLE. When this occurs, T and B cells are activated in an uncontrolled manner and produce autoantibodies against self fragmented DNA, RNA and sometimes other parts of the cell such as cardiolipin, phosphatidylserine, etc.</p><p>The mechanism behind the breakdown of self-tolerance may be genetic factors that are triggered by environmental factors. SLE is not caused by a single gene, but by many genes, and is thus a polygenic disease. So far only a few genes have been found to be associated with SLE including PDCD1, FcγRs, and PTPN22. The main aim of my thesis is to find susceptibility genes responsible for SLE.</p><p>Recently, a gene called IRF5 was found to be associated with SLE. In paper one, we performed a thorough study and confirmed its association to SLE. In addition, we found a few other SNPs in the gene that were associated to the disease. Among them, SNP rs2004640 is very strongly associated and was found to affect the splicing of the gene. Another SNP, rs2280714, correlated with overexpression of the gene, although SNP rs10954213 was much more highly correlated with expression adding to this, in paper two we found a few other SNPs that were associated to SLE and played crucial roles in gene function. An indel in exon 6, though not associated by itself, regulated which isoforms were expressed. Individuals with 2 repeats expressed isoforms V1 and V4, while individuals with 4 repeats expressed isoforms V5 and V6. SNP rs2070197 was also very strongly associated, but did not have a functional role. In paper three, the same polymorphisms were studied in a Mexican population, which showed an even stronger association when compared to a European population.</p><p>It is known that autoimmune diseases share susceptibility genes, therefore we wanted to see if the IRF5 gene is associated with any other autoimmune diseases. In papers four and five, we tested its association to RA (using three sets of patients and controls from Sweden, Argentina and Spain) and psoriasis (using a set of patients and controls from Sweden). Association was not found in either of the diseases. Therefore, we believe that this association may be SLE-specific.</p>

The breakdown of self-tolerance is the main driving force behind susceptibility to SLE. When this occurs, T and B cells are activated in an uncontrolled manner and produce autoantibodies against self fragmented DNA, RNA and sometimes other parts of the cell such as cardiolipin, phosphatidylserine, etc. The mechanism behind the breakdown of self-tolerance may be genetic factors that are triggered by environmental factors. SLE is not caused by a single gene, but by many genes, and is thus a polygenic disease. So far only a few genes have been found to be associated with SLE including PDCD1, FcγRs, and PTPN22. The main aim of my thesis is to find susceptibility genes responsible for SLE. Recently, a gene called IRF5 was found to be associated with SLE. In paper one, we performed a thorough study and confirmed its association to SLE. In addition, we found a few other SNPs in the gene that were associated to the disease. Among them, SNP rs2004640 is very strongly associated and was found to affect the splicing of the gene. Another SNP, rs2280714, correlated with overexpression of the gene, although SNP rs10954213 was much more highly correlated with expression adding to this, in paper two we found a few other SNPs that were associated to SLE and played crucial roles in gene function. An indel in exon 6, though not associated by itself, regulated which isoforms were expressed. Individuals with 2 repeats expressed isoforms V1 and V4, while individuals with 4 repeats expressed isoforms V5 and V6. SNP rs2070197 was also very strongly associated, but did not have a functional role. In paper three, the same polymorphisms were studied in a Mexican population, which showed an even stronger association when compared to a European population. It is known that autoimmune diseases share susceptibility genes, therefore we wanted to see if the IRF5 gene is associated with any other autoimmune diseases. In papers four and five, we tested its association to RA (using three sets of patients and controls from Sweden, Argentina and Spain) and psoriasis (using a set of patients and controls from Sweden). Association was not found in either of the diseases. Therefore, we believe that this association may be SLE-specific.

La spondyloarthrite (SpA) est un rhumatisme inflammatoire chronique fréquent et invalidant. Plus d’une vingtaine de locus de susceptibilité à la maladie ont été identifiés à ce jour, dont HLA-B27 situé dans le complexe majeur d’histocompatibilité (CMH). L’objectif de ce travail était d’identifier de nouveaux facteurs génétiques de susceptibilité à la SpA grâce à une double approche d’études familiales et de génomique fonctionnelle. Dans la première partie, nous avons génotypé des familles multiplex de SpA. L’analyse de liaison non paramétrique a révélé la présence, en plus du CMH, d’un nouveau locus significativement lié à la SpA en 13q13. L’étude de ce locus nous a permis de restreindre la région d’intérêt à un intervalle de 1,3 Mb, dont le séquençage est en cours. Par ailleurs, l’étude d’association intra-familiale a identifié un SNP intronique de MAPK14 significativement associé à la SpA. Enfin, nous avons montré que l’un des SNPs du gène IL23R connu pour être associé à la spondylarthrite ankylosante était en fait associé à la présence d’une sacro-iliite radiologique dans la SpA. Parallèlement aux études familiales, nous avons comparé le transcriptome de cellules dendritiques de neuf patients atteints de SpA à celui de dix témoins sains. Nous avons ainsi identifié 81 gènes différentiellement exprimés. Nous avons aussi montré que l’expression génique d’ERAP1 (et à un moindre degré son expression protéique et son niveau d’activité enzymatique) étaient sous le contrôle de polymorphismes de ce gène associés à la SpA. / Spondyloarthritis (SpA) is a frequent and disabling chronic rheumatic disease. To date, more than 20 susceptibility loci have been identified, including HLA-B27 in the major histocompatibility complex (MHC). Most of the disease heritability remains to be elucidated. The aim of the study was to identify new genetic factors of susceptibility to SpA using an approach combining genetics and functional genomics. In the first part of this work, we genotyped SpA multiplex families with microarrays of 250,000 SNPs. Non parametric linkage analysis revealed a new locus significantly linked to SpA outside the MHC, in 13q13. Further studies on this locus allowed us to map the disease interval to a 1.3 Mb region, which will be soon sequenced. Moreover, family-based association study identified a significant association between one intronic SNP in MAPK14 and SpA. We also showed that one of the known ankylosing spondylitis-associated SNP in IL23R was indeed associated with sacroiliitis in SpA. We have also compared dendritic cells gene expression between nine SpA patients and ten controls and identified 81 genes differentially expressed. Moreover, we showed that ERAP1 gene expression (and at a less extent protein expression and enzymatic activity) is under the control of several polymorphisms in the gene which has previously been associated with SpA.

Assortative Mating, the tendency for mate selection to occur on the basis of similar traits, plays an essential role in understanding the genetic variation on academic achievements and intelligence (IQ). It is an important mechanism explaining spousal concordance. We used principal component analysis (PCA) for spousal correlation. There is a significant positive correlation between spouses by the new variable PC1 (correlation coefficient=0.515, p<0.0001). We further research the genetic factor that affects IQ by using the same data. We performed a low density genome-wide association (GWA) analysis with a family-based association test to identify genetic variants that associated with intelligence as measured by WAIS full-score IQ (FSIQ). NTM at 11q25 (rs411280, p=0.000764) and NR3C2 at 4q31.23 (rs3846329, p=0.000675) were 2 novel genes that haven't been associated with IQ from other studies. This study may serve as a resource for replication in other populations and a foundation for future investigations.