Meta-Analysis of Genome-Wide Linkage Studies in Celiac Disease.

OBJECTIVE: A meta-analysis of genome-wide linkage studies allows us to summarize the extensive information available from family-based studies, as the field moves into genome-wide association studies. METHODS: Here we apply the genome scan meta-analysis (GSMA) method, a rank-based, model-free approach, to combine results across eight independent genome-wide linkages performed on celiac disease (CD), including 554 families with over 1,500 affected individuals. We also investigate the agreement between signals we identified from this meta-analysis of linkage studies and those identified from genome-wide association analysis using a hypergeometric distribution. RESULTS: Not surprisingly, the most significant result was obtained in the HLA region. Outside the HLA region, suggestive evidence for linkage was obtained at the telomeric region of chromosome 10 (10q26.12-qter; p = 0.00366), and on chromosome 8 (8q22.2-q24.21; p = 0.00491). Testing signals of association and linkage within bins showed no significant evidence for co-localization of results. CONCLUSION: This meta-analysis allowed us to pool the results from available genome-wide linkage studies and to identify novel regions potentially harboring predisposing genetic variation contributing to CD. This study also shows that linkage and association studies may identify different types of disease-predisposing variants

Molecular genetic analysis for malignant hyperthermia : a thesis presented to Massey University in partial fulfilment of the requirements for the degree of Master of Science in Biochemistry

Malignant hyperthermia (MH) is a rare pharmacogenetic disorder in humans caused by inhalational general anaesthetics and depolarising muscle relaxants. An MH reaction shows abnormal calcium homeostasis in skeletal muscle leading to a hypermetabolic state and increased muscle contracture. A mutation within the calcium release channel ryanodine receptor of skeletal muscle (RYR1) is one of the causes of MH leading to the abnormally high release of calcium ions into the cytosol during MH reactions. The MH reaction can also be triggered by excess exercise, heat and stress. A New Zealand male, identified as M818, showed a fulminant MH reaction which resulted in death. The reaction was caused by exercise, and he did not have a family history of MH. As this individual did not have any of the mutations within RYR1 found to date in New Zealand families, the entire RYR1 cDNA was screened for a novel mutation that may result in susceptibility to exercise-induced MH. This patient may have had a novel RYRl mutation because exercise-induced MH is quite rare. Screening of this gene, however did not identify any mutations within RYR1 suggesting that the M818 patient may have a mutation in another gene because MH is a heterogeneous disorder with 40-50% of families showing linkage to alternative loci. Heterogeneity of MH can result in discordance between genotype and phenotype. Some MH susceptible patients do not have a RYR1 mutation that is found in other individuals with the same kindred. One or more other genes could be associated with MH for these individuals although alternative loci have not been studied in New Zealand families. A genome-wide scan was performed to search for other candidate loci using a large MH kindred known as the CH family within which discordance has been observed. Non-parametric linkage analysis across all chromosomes identified five weak linkages from one branch, and two strong linkages from another branch of the CH family. Secondary linkage analysis was performed on one candidate locus identified in the genome-wide scan, and a weak linkage and recombination was observed within the shorter region. No candidate genes with obvious relevance to calcium homeostasis or signalling were identified within this region. The existence of alternative causative loci in this family cannot be ruled out however, because the loci identified from the genome-wide scan are very large and contain many genes of unknown function

A Meta-Analysis of Genome-Wide Association Scans Identifies IL18RAP, PTPN2, TAGAP, and PUS10 As Shared Risk Loci for Crohn's Disease and Celiac Disease

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Study of congenital Morgagnian cataracts in Holstein calves

Cataracts are focal to diffuse opacities of the eye lens causing impaired vision or complete blindness. For bilateral congenital cataracts in Red Holsteins a perfectly cosegregating mutation within the CPAMD8 gene (CPAMD8:g.5995966C>T) has been reported. We genotyped the CPAMD8:g.5995966C>T variant in Holstein calves affected by congenital bilateral congenital cataracts, their unaffected relatives and randomly selected herd mates. Ophthalmological examinations were performed in all affected individuals to confirm a congenital cataract. Whole genome sequencing was employed to screen variants in candidate genes for the Morgagnian cataract phenotype. In the present study, 3/35 cases were confirmed as homozygous mutated and 6/14 obligate carriers. Further 7/46 unaffected animals related with these cases were heterozygous mutated for the CPAMD8:g.5995966C>T variant. However 32 cases with a congenital cataract showed the wild type for the CPAMD8 variant. We did not identify variants in the candidate genes CPAMD8 and NID1 or in their close neighborhood as strongly associated with the congenital cataract phenotype in Holstein calves with the CPAMD8 wild type. In conclusion, the CPAMD8:g.5995966C>T variant is insufficient to explain the majority of Morgagnian congenital cataract phenotypes in Holsteins. It is very likely that congenital bilateral cataracts may be genetically heterogeneous and not yet known variants in genes other than CPAMD8 and NID1 are involved