A novel locus for adolescent idiopathic scoliosis on chromosome 12p.

Adolescent idiopathic scoliosis (AIS) is a common disorder with strong evidence for genetic predisposition. Quantitative trait loci (QTLs) for AIS susceptibility have been identified on chromosomes. We performed a genome-wide genetic linkage scan in seven multiplex families using 400 marker loci with a mean spacing of 8.6 cM. We used Genehunter Plus to generate linkage statistics, expressed as homogeneity (HLOD) scores, under dominant and recessive genetic models. We found a significant linkage signal on chromosome 12p, whose support interval extends from near 12 pter, spanning approximately 10 million bases or 31 cM. Fine mapping within the region using 20 additional markers reveals maximum HLOD = 3.7 at 5 cM under a dominant inheritance model, and a split peak maximum HLOD = 3.2 at 8 and 18 cM under a recessive inheritance model. The linkage support interval contains 95 known genes. We found evidence suggestive of linkage on chromosomes 1, 6, 7, 8, and 14. This study is the first to find evidence of an AIS susceptibility locus on chromosome 12. Detection of AIS susceptibility QTLs on multiple chromosomes in this and other studies demonstrate that the condition is genetically heterogeneous.

Combining gene expression, demographic and clinical data in modeling disease: a case study of bipolar disorder and schizophrenia.

BACKGROUND: This paper presents a retrospective statistical study on the newly-released data set by the Stanley Neuropathology Consortium on gene expression in bipolar disorder and schizophrenia. This data set contains gene expression data as well as limited demographic and clinical data for each subject. Previous studies using statistical classification or machine learning algorithms have focused on gene expression data only. The present paper investigates if such techniques can benefit from including demographic and clinical data. RESULTS: We compare six classification algorithms: support vector machines (SVMs), nearest shrunken centroids, decision trees, ensemble of voters, naïve Bayes, and nearest neighbor. SVMs outperform the other algorithms. Using expression data only, they yield an area under the ROC curve of 0.92 for bipolar disorder versus control, and 0.91 for schizophrenia versus control. By including demographic and clinical data, classification performance improves to 0.97 and 0.94 respectively. CONCLUSION: This paper demonstrates that SVMs can distinguish bipolar disorder and schizophrenia from normal control at a very high rate. Moreover, it shows that classification performance improves by including demographic and clinical data. We also found that some variables in this data set, such as alcohol and drug use, are strongly associated to the diseases. These variables may affect gene expression and make it more difficult to identify genes that are directly associated to the diseases. Stratification can correct for such variables, but we show that this reduces the power of the statistical methods.

Quantitative trait locus analysis of carotid atherosclerosis in an intercross between C57BL/6 and C3H apolipoprotein E-deficient mice.

BACKGROUND AND PURPOSE: Inbred mouse strains C57BL/6J (B6) and C3H/HeJ (C3H) exhibit marked differences in atherosclerotic lesion formation in the carotid arteries on the apolipoprotein E-deficient (apoE(-/-)) background when fed a Western diet. Quantitative trait locus analysis was performed on an intercross between B6.apoE(-/-) and C3H.apoE(-/-) mice to determine genetic factors contributing to variation in the phenotype. METHODS: Female B6.apoE(-/-) mice were crossed with male C3H.apoE(-/-) mice to generate F(1) hybrids, which were intercrossed to generate 241 female F(2) progeny. At 6 weeks of age, F(2) mice were started on a Western diet. After being fed the diet for 12 weeks, F(2) mice were analyzed for phenotypes such as lesion size in the left carotid arteries and plasma lipid levels and typed for 154 genetic markers spanning the mouse genome. RESULTS: One significant quantitative trait locus, named CAth1 (25 cM, log of the odds score: 4.5), on chromosome 12 and 4 suggestive quantitative trait loci, on chromosomes 1, 5, 6, and 11, respectively, were identified to influence carotid lesion size. One significant quantitative trait locus on distal chromosome 1 accounted for major variations in plasma low-density lipoprotein/very-low-density lipoprotein, high-density lipoprotein cholesterol, and triglyceride levels. Carotid lesion size was not significantly correlated with plasma low-density lipoprotein/very-low-density lipoprotein or high-density lipoprotein cholesterol levels. CONCLUSIONS: These data indicate that the loci for carotid lesions do not overlap with those for aortic lesions as identified in a previous cross derived from the same parental strains, and carotid atherosclerosis and plasma lipids are controlled by separate genetic factors in the B6 and C3H mouse model.

Clinical applications of whole-genome association studies: future applications at the bedside.

Until now, performing whole-genome association studies has been an unattainable, but highly desirable, goal for geneticists. With the recent advent of high-throughput genotyping platforms, this goal is now a reality for geneticists today and for clinicians in the not-so-distant future. This review will cover a broad range of topics to provide an overview of this emerging branch of genetics, and will provide references to more specific sources. Specifically, this review will cover the technologies available today and in the near future, the specific types of whole-genome association studies, the benefits and limitations of these studies, the applications to complex disease-gene interactions, diagnostic devices, therapeutics, and finally, we will describe the 5-year perspective and key issues.

Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2.

Contactin-associated protein-like 2 (CASPR2) is encoded by CNTNAP2 and clusters voltage-gated potassium channels (K(v)1.1) at the nodes of Ranvier. We report a homozygous mutation of CNTNAP2 in Old Order Amish children with cortical dysplasia, focal epilepsy, relative macrocephaly, and diminished deep-tendon reflexes. Intractable focal seizures began in early childhood, after which language regression, hyperactivity, impulsive and aggressive behavior, and mental retardation developed in all children. Resective surgery did not prevent the recurrence of seizures. Temporal-lobe specimens showed evidence of abnormalities of neuronal migration and structure, widespread astrogliosis, and reduced expression of CASPR2.

Mapping of sudden infant death with dysgenesis of the testes syndrome (SIDDT) by a SNP genome scan and identification of TSPYL loss of function.

We have identified a lethal phenotype characterized by sudden infant death (from cardiac and respiratory arrest) with dysgenesis of the testes in males [Online Mendelian Inheritance in Man (OMIM) accession no. 608800]. Twenty-one affected individuals with this autosomal recessive syndrome were ascertained in nine separate sibships among the Old Order Amish. High-density single-nucleotide polymorphism (SNP) genotyping arrays containing 11,555 single-nucleotide polymorphisms evenly distributed across the human genome were used to map the disease locus. A genome-wide autozygosity scan localized the disease gene to a 3.6-Mb interval on chromosome 6q22.1-q22.31. This interval contained 27 genes, including two testis-specific Y-like genes (TSPYL and TSPYL4) of unknown function. Sequence analysis of the TSPYL gene in affected individuals identified a homozygous frameshift mutation (457_458insG) at codon 153, resulting in truncation of translation at codon 169. Truncation leads to loss of a peptide domain with strong homology to the nucleosome assembly protein family. GFP-fusion expression constructs were constructed and illustrated loss of nuclear localization of truncated TSPYL, suggesting loss of a nuclear localization patch in addition to loss of the nucleosome assembly domain. These results shed light on the pathogenesis of a disorder of sexual differentiation and brainstem-mediated sudden death, as well as give insight into a mechanism of transcriptional regulation.

Integrating microarrays into disease-gene identification strategies.

Positional cloning represents one of the most successful paradigm shifts in identifying the underlying patho-mechanisms in human disease. While traditional discovery tools focused on identifying defects at the tissue or cellular level, positional cloning identifies the damaged region of the genome as the preliminary step. While a large number of inherited single gene disorders have been mapped using this approach, a bottleneck still exists in combing through the genomic interval, often millions of nucleotides in length, to identify the nucleotide changes which result in a defective protein and subsequent disease. Along with the recent unravelling of the human genetic code, the development of massively parallel tools, such as microarrays, represent an equally important step forward in unraveling pathogenic genome dysfunctions. There are many emerging variants on microarray technology, such as expression arrays, exon arrays, array-based comparative genomic hybridization and sequencing arrays. Several of these platforms, if used properly, can accelerate the positional cloning process. The proper use of the platform is driven by knowledge of the underlying molecular defect being searched for and the operating characteristics of the array. The resultant insight forms the basis for improved molecular diagnostics and novel therapeutic targets.