Common variations in ALG9 are not associated with bipolar I disorder: A family-based study

Background: A mannosyltransferase gene (ALG9, DIBD I) at chromosome band 11q23 was previously identified to be disrupted by a balanced chromosomal translocation t(9; 11)(p24;q23) co-segregating with bipolar affective disorder in a small family. Inborn ALG9 deficiency (congenital disorders of glycosylation type IL) is associated with progressive microcephaly, seizures, developmental delay, and hepatomegaly. It is unknown whether common variations of ALG9 predispose to bipolar affective disorder. Methods: We tested five polymorphic markers spanning ALG9 (three intragenic and one upstream microsatellite repeats and one common missense variation, V2891 (rs10502151) for their association with bipolar I disorder in two pedigree series. The NIMH (National Institute of Mental Health) pedigrees had a total of 166 families showing transmissions to 250 affected offspring, whereas The PITT (The University of Pittsburgh) pedigrees had a total of 129 families showing transmissions to 135 cases. We used transmission disequilibrium test for the association analyses. Results: We identified three common and distinct haplotypes spanning the ALG9 gene. We found no statistically-significant evidence of transmission disequilibrium of marker alleles or multi-marker haplotypes to the affected offspring with bipolar I disorder. Conclusion: These results suggest that common variations in ALG9 do not play a major role in predisposition to bipolar affective disorder. © 2006 Baysal et al; licensee BioMed Central Ltd

Hepatic differentiation of human pluripotent stem cells in miniaturized format suitable for high-throughput screen

AbstractThe establishment of protocols to differentiate human pluripotent stem cells (hPSCs) including embryonic (ESC) and induced pluripotent (iPSC) stem cells into functional hepatocyte-like cells (HLCs) creates new opportunities to study liver metabolism, genetic diseases and infection of hepatotropic viruses (hepatitis B and C viruses) in the context of specific genetic background. While supporting efficient differentiation to HLCs, the published protocols are limited in terms of differentiation into fully mature hepatocytes and in a smaller-well format. This limitation handicaps the application of these cells to high-throughput assays. Here we describe a protocol allowing efficient and consistent hepatic differentiation of hPSCs in 384-well plates into functional hepatocyte-like cells, which remain differentiated for more than 3weeks. This protocol affords the unique opportunity to miniaturize the hPSC-based differentiation technology and facilitates screening for molecules in modulating liver differentiation, metabolism, genetic network, and response to infection or other external stimuli

Reproducibility of gene expression across generations of Affymetrix microarrays

BACKGROUND: The development of large-scale gene expression profiling technologies is rapidly changing the norms of biological investigation. But the rapid pace of change itself presents challenges. Commercial microarrays are regularly modified to incorporate new genes and improved target sequences. Although the ability to compare datasets across generations is crucial for any long-term research project, to date no means to allow such comparisons have been developed. In this study the reproducibility of gene expression levels across two generations of Affymetrix GeneChips(® )(HuGeneFL and HG-U95A) was measured. RESULTS: Correlation coefficients were computed for gene expression values across chip generations based on different measures of similarity. Comparing the absolute calls assigned to the individual probe sets across the generations found them to be largely unchanged. CONCLUSION: We show that experimental replicates are highly reproducible, but that reproducibility across generations depends on the degree of similarity of the probe sets and the expression level of the corresponding transcript

Genetic Overlap Profiles of Cognitive Ability in Psychotic and Affective Illnesses: A Multisite Study of Multiplex Pedigrees

Background: Cognitive impairment is a key feature of psychiatric illness, making cognition an important tool for exploring of the genetics of illness risk. It remains unclear which measures should be prioritized in pleiotropy-guided research. Here, we generate profiles of genetic overlap between psychotic and affective disorders and cognitive measures in Caucasian and Hispanic groups. Methods: Data were from 4 samples of extended pedigrees (N = 3046). Coefficient of relationship analyses were used to estimate genetic overlap between illness risk and cognitive ability. Results were meta-analyzed. Results: Psychosis was characterized by cognitive impairments on all measures with a generalized profile of genetic overlap. General cognitive ability shared greatest genetic overlap with psychosis risk (average endophenotype ranking value [ERV] across samples from a random-effects meta-analysis = 0.32), followed by verbal memory (ERV = 0.24), executive function (ERV = 0.22), and working memory (ERV = 0.21). For bipolar disorder, there was genetic overlap with processing speed (ERV = 0.05) and verbal memory (ERV = 0.11), but these were confined to select samples. Major depressive disorder was characterized by enhanced working and face memory performance, as reflected in significant genetic overlap in 2 samples. Conclusions: There is substantial genetic overlap between risk for psychosis and a range of cognitive abilities (including general intelligence). Most of these effects are largely stable across of ascertainment strategy and ethnicity. Genetic overlap between affective disorders and cognition, on the other hand, tends to be specific to ascertainment strategy, ethnicity, and cognitive test battery

Role of miRNA binding site SNPs in candidate genes in a North Indian schizophrenia cohort

Schizophrenia (SZ) is a debilitating neuropsychiatric disorder with ~80% heritability. Despite several genetic studies including linkage and candidate gene association and more recently GWAS, which have identified several risk variants, the total heritability of SZ remains elusive. In addition, a number of gene expression studies have reported dysregulation of candidate genes both in brain and blood of SZ cases compared to controls. Although, the role of coding, promoter, intergenic and UTR SNPs, have been demonstrated, very little is known about the role of miRNA binding site SNPs. In this study, we undertook to investigate the association, if any, of this important class of regulatory variants with SZ. Using in silico prediction tools, 27 functionally relevant SNPs from around 150 candidate genes were prioritized and genotyped in a north Indian SZ cohort (n=507 cases; n=522 controls).\ud \ud Test of association of these SNPs showed only one variant rs7430 in PPP3CC to be associated (p=0.01) with SZ. Analysis of genotype data in a subset of patients (TD positive n=89; TD negative n=160) with Tardive dyskinesia (TD), an iatrogenic disorder of SZ, showed association of rs4846049 in MTHFR (p=0.04) & rs17881908 in GCLM (p= 0.05 ) with this condition. Further regression analysis of the genotype data with neurocognitive measures in a subset (cases n=152; controls n=290) of the study cohort, showed significant association of nine SNPs (p< 0.05) with different domains of cognition. Based on this moderately powered study, the contribution of miRNA binding site SNPs in candidate genes to SZ and to TD seems negligible. However, their promising contribution to cognitive parameters warrants additional investigations

Rediscovering the value of families for psychiatric genetics research

As it is likely that both common and rare genetic variation are important for complex disease risk, studies that examine the full range of the allelic frequency distribution should be utilized to dissect the genetic influences on mental illness. The rate limiting factor for inferring an association between a variant and a phenotype is inevitably the total number of copies of the minor allele captured in the studied sample. For rare variation, with minor allele frequencies of 0.5% or less, very large samples of unrelated individuals are necessary to unambiguously associate a locus with an illness. Unfortunately, such large samples are often cost prohibitive. However, by using alternative analytic strategies and studying related individuals, particularly those from large multiplex families, it is possible to reduce the required sample size while maintaining statistical power. We contend that using whole genome sequence (WGS) in extended pedigrees provides a cost-effective strategy for psychiatric gene mapping that complements common variant approaches and WGS in unrelated individuals. This was our impetus for forming the “Pedigree-Based Whole Genome Sequencing of Affective and Psychotic Disorders” consortium. In this review, we provide a rationale for the use of WGS with pedigrees in modern psychiatric genetics research. We begin with a focused review of the current literature, followed by a short history of family-based research in psychiatry. Next, we describe several advantages of pedigrees for WGS research, including power estimates, methods for studying the environment, and endophenotypes. We conclude with a brief description of our consortium and its goals