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- Blomqvist, Mia E-L, et al.
(författare)
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Towards compendia of negative genetic association studies: an example for Alzheimer disease.
- 2006
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Ingår i: Human genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 119:1-2, s. 29-37
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Tidskriftsartikel (refereegranskat)abstract
- Most genetic sequence variants that contribute to variability in complex human traits will have small effects that are not readily detectable with population samples typically used in genetic association studies. A potentially valuable tool in the gene discovery process is meta-analysis of the accumulated published data, but in order to be valid these require a sample of studies representative of the true genetic effect and thus hypothetically should include some positive and an abundance of negative reports. A survey of the literature on association studies for Alzheimer disease (AD) from January 2004-April 2005, identified 138 studies, 86 of which reported positive findings other than for apolipoprotein E (APOE), strongly indicative of publication bias. We report here an analysis of 62 genetic markers, tested for association with AD risk as well as for possible effects upon quantitative indices of AD severity (mini-mental state examination scores, age-at-onset, and cerebrospinal fluid (CSF) beta-amyloid (Abeta) and CSF tau proteins). Within this set, only modest signals were present that, with the exception of APOE are easily lost when corrections for multiple hypotheses are applied. In isolation, results are thus broadly negative. Genes studied encompass both novel candidates as well as several recently claimed to be associated with AD (e.g. urokinase plasminogen activator (PLAU) and acetyl-coenzyme A acetyltransferase 1 (ACAT1)). By reporting these data we hope to encourage the publication of gene compendia to guide further studies and aid future meta-analyses aimed at resolving the involvement of genes in complex human traits.
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| 4. |
- Engelmark, Malin, et al.
(författare)
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Polymorphisms in 9q32 and TSCOT are linked to cervical cancer in affected sib-pairs with high mean age at diagnosis
- 2008
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 123:5, s. 437-443
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Tidskriftsartikel (refereegranskat)abstract
- Cervical cancer is a multifactorial disease influenced by both environmental and genetic factors. We have previously found linkage to 9q32 in a genomewide scan of affected sib-pairs (ASPs) with cervical cancer and to the thymic stromal co-transporter (TSCOT), a candidate gene in this region. Here we examined the contribution of 9q32 and TSCOT to cervical cancer susceptibility using at larger material of 641 ASPs, 278 of which were included in the earlier genome-scan. Since heritable forms of cancer frequently show stronger genetic effects in families with early onset of disease, we stratified the ASPs into two groups based on mean age at diagnosis (MAAD) within sib-pairs. Surprisingly, ASPs with high MAAD (30.5-47.5 years) showed increased sharing at all microsatellite markers at 9q31.1-33.1 and linkage signals of up to MLS = 2.74 for TSCOT SNPs, while ASPs with low MAAD (19-30 years) showed no deviation from random genetic sharing (MLS = 0.00). The difference in allelic sharing between the two MAAD strata was significant (P < 0.005) and is not likely to be explained by the HLA haplotype, a previously known genetic susceptibility factor for cervical cancer. Our results indicate locus heterogeneity in the susceptibility to cervical cancer between the two strata, with polymorphisms in the 9q32 region mainly showing an effect in women with high MAAD.
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| 6. |
- Hertz, J M, et al.
(författare)
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Alport syndrome caused by inversion of a 21 Mb fragment of the long arm of the X-chromosome comprising exon 9 through 51 of the COL4A5 gene
- 2005
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 1432-1203 .- 0340-6717. ; 118:1, s. 23-28
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Tidskriftsartikel (refereegranskat)abstract
- The X-linked form of Alport syndrome (AS) is caused by mutation in the COL4A5 gene located at Xq22.3 and encoding the alpha 5-chain of type IV-collagen. More than 400 different mutations have so far been detected in the COL4A5 gene. Not all mutations, however, will be detected using an exon-by-exon mutation detection strategy such as SSCP analysis or direct sequencing. We have previously reported the results of SSCP analysis of 81 patients suspected of X-linked AS. Genomic DNA from these 81 patients was also analyzed for larger genomic rearrangements, using Southern blotting analysis. Abnormal band patterns were found in three patients, two of which were caused by single base substitutions in the coding region, also detected by the SSCP analysis. Here we report the results of the analysis of a larger structural COL4A5 rearrangement that escaped the SSCP analysis. The rearrangement was found to be an inversion of a 21 Mb fragment of the COL4A5 gene comprising exon 9 through 51 with proximal breakpoint within intron 8 at Xq22.3 and a distal breakpoint 56 kb upstream to the initiation codon in the RAB33A gene at Xq25. The inversion of exon 9 through 51 is expected to result in a truncated or absent alpha 5(IV)chain and has not previously been associated with AS. These findings emphasize the need for a supplement to mutation detection strategies such as SSCP analysis and direct sequencing, in order to detect more complicated structural COL4A5 rearrangements. Larger structural rearrangements constitute 2.3% (1/43) of the mutations in the present material.
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| 8. |
- Hmani-Aifa, Mounira, et al.
(författare)
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A genome-wide linkage scan in Tunisian families identifies a novel locus for non-syndromic posterior microphthalmia to chromosome 2q37.1
- 2009
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Ingår i: HUMAN GENETICS. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 126:4, s. 575-587
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Tidskriftsartikel (refereegranskat)abstract
- Posterior microphthalmia (PM) is a relatively rare autosomal recessive condition with normal anterior segment and small posterior segment resulting in high hyperopia and retinal folding. It is an uncommon subtype of microphthalmia that has been mostly reported to coexist with several other ophthalmic conditions and to occur in sporadic cases. The membrane-type frizzled-related protein (MFRP) is the only gene so far reported implicated in autosomal recessive, non-syndromic and syndromic forms of PM. Here, we performed a clinical and genetic analysis using six consanguineous families ascertained from different regions of Tunisia and affected with non-syndromic PM that segregates as an autosomal recessive trait. To identify the disease-causing defect in these families, we first analysed MFRP gene, then some candidate genes (CHX10, OPA1, MITF, SOX2, CRYBB1-3 and CRYBA4) and loci (MCOP1, NNO1 and NNO2) previously implicated in different forms of microphthalmia. After exclusion of these genes and loci, we performed a genome-wide scan using a high density single nucleotide polymorphism (SNP) array 50 K in a large consanguineous pedigree. SNP genotyping revealed eight homozygous candidate regions on chromosomes 1, 2, 3, 6, 15, 17 and 21. Linkage analysis with additional microsatellite markers only retained the 2q37.1 region with a maximum LOD score of 8.85 obtained for D2S2344 at theta = 0.00. Further investigations are compatible for linkage of four more families to this region with a refined critical interval of 2.35 Mb. The screening of five candidate genes SAG, PDE6D, CHRND, CHRNG and IRK13 did not reveal any disease-causing mutation.
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| 10. |
- Johansson, Asa, et al.
(författare)
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Linkage disequilibrium between microsatellite markers in the Swedish Sami relative to a worldwide selection of populations
- 2005
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 116:1-2, s. 105-13
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Tidskriftsartikel (refereegranskat)abstract
- The pattern of linkage disequilibriurn (LD) is affected by a number of factors, including population dernography. High LD is seen in populations with a relatively limited and constant size, presurnably due to genetic drift. We have examined the extent of LD arnong over 300 genome-wide pattern microsatellite loci in 29 populations from around the world. The pattern of LD vari ed between populations, with larger extent of LO in populations with limited size relative to larger populations. In addition, the LD between 88 less spaced microsatellite ffiarkers from 10 different genornic regions were examined in the Sami compared to the general Swedish population. For the se ffiarkers increased LD extending up to 5 Mb was detected in the Sami. The arnount of LD also differed between the chrornosornal regions. The arnount of LD in the Sami makes this population suited for mapping ofcornplex genetic traits
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