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Anjali K. Henders, Allan F McRae and Grant W. Montogomery were involved in the generation of the data used for the study. Joseph E. Powell, Allan F. ... A Ljung-Box test  was used to test for significant levels of autocorrelation in the g(s) estimates: Q ¼ nðn þ 2Þ X h k¼1r 2 k n À k ð6Þ Where n is the sample size, k is the lag,r k is the autocorrelation ...doi:10.1371/journal.pone.0126995 pmid:26023781 pmcid:PMC4449160 fatcat:5e3ckkkuyvhzva6qgxczcckzpi
BMC Medical Genomics
Expression quantitative trait loci (eQTL) are genomic regions regulating RNA transcript expression levels. Genome-wide Association Studies (GWAS) have identified many variants, often in non-coding regions, with unknown functions and eQTL provide a possible mechanism by which these variants may influence observable phenotypes. Limited access and availability of tissues such as brain has led to the use of blood as a substitute for eQTL analyses. Methods: Here, we evaluate the overlap of eQTLdoi:10.1186/1755-8794-7-31 pmid:24894490 pmcid:PMC4066287 fatcat:baxl4kzxmzfmpgte4xuxmjkf2a
more »... ted in published studies conducted in blood and brain tissues to assess the utility of blood as an alternative to brain tissue in the study of neurological and psychiatric conditions. Expression QTL results from eight published brain studies were compared to blood eQTL identified in from a meta-analysis involving 5,311 individuals. We accounted for differences in SNP platforms and study design by using SNP proxies in high linkage disequilibrium with reported eQTL. The degree of overlap between studies was calculated by ascertaining if an eQTL identified in one study was also identified in the other study. Results: The percentage of eQTL overlapping for brain and blood expression after adjusting for differences in sample size ranged from 13 -23% (mean 19.2%). Amongst pairs of brain studies eQTL overlap ranged from 0 -35%, with higher degrees of overlap found for studies using expression data collected from the same brain region. Conclusion: Our results suggest that whenever possible tissue specific to the pathophysiology of the disease being studied should be used for transcription analysis.
The methylation data was accessed through Bioconductor FlowSorted.Blood.450 k package. ...doi:10.1186/s12864-016-2498-4 pmid:27048375 pmcid:PMC4822256 fatcat:ffccud42kja5zbvoqpgadx6g6i
Hemani et al. We thank Wood et al. for their interesting observations but do not believe that their overall conclusions are consistent with the results presented. First, although we replicate our results in large, independent samples, they do not replicate 19/30 of our reported interactions ( Table 1 in ) in the InCHIANTI dataset (N=450) at a type-I error rate of 0.05/30=0.002, including none of our reported cis-trans interactions. Despite having insufficient data to draw conclusions on thedoi:10.1038/nature13692 pmid:25279929 pmcid:PMC4404158 fatcat:4fp6sxuhzbflthwn76f4wbslrq
more »... is-trans effects, Wood et al. claim that this alternative explanation implies that there remains 'no compelling evidence for widespread epistasis in humans'. Second, applying their method in our discovery and replication datasets  fails to abrogate the statistical evidence for epistasis. Specifically, the meta-analysis of these results shows that interaction effects remain for 24/26 epistasis pairs after correcting for effects of the IncSeq SNP (Table 1) . For the remaining two pairs (at CSTB and LAX1) we cannot rule out a haplotype effect such as postulated by Wood et al. and this may indeed be a more parsimonious explanation for these two pairs. Haplotype effects are known to be confounding factors in cis-cis interactions, as stated in Hemani et al. Third, Wood et al. ignore the possibility that the IncSeq SNP is either one of the epistatic causal loci, or in higher LD with the causal loci than the genotyped epistatic SNP and
Principal components analysis has been employed in gene expression studies to correct for population substructure and batch and environmental effects. This method typically involves the removal of variation contained in as many as 50 principal components (PCs), which can constitute a large proportion of total variation present in the data. Each PC, however, can detect many sources of variation, including gene expression networks and genetic variation influencing transcript levels. Wedoi:10.1534/genetics.113.153221 pmid:24026092 pmcid:PMC3813841 fatcat:nzf5c3d725fwxge22zdesxm7qi
more »... that PCs generated from gene expression data can simultaneously contain both genetic and nongenetic factors. From heritability estimates we show that all PCs contain a considerable portion of genetic variation while nongenetic artifacts such as batch effects were associated to varying degrees with the first 60 PCs. These PCs demonstrate an enrichment of biological pathways, including core immune function and metabolic pathways. The use of PC correction in two independent data sets resulted in a reduction in the number of cis- and trans-expression QTL detected. Comparisons of PC and linear model correction revealed that PC correction was not as efficient at removing known batch effects and had a higher penalty on genetic variation. Therefore, this study highlights the danger of eliminating biologically relevant data when employing PC correction in gene expression data.
The mitochondrial and nuclear genomes coordinate and co-evolve in eukaryotes in order to adapt to environmental changes. Variation in the mitochondrial genome is capable of affecting expression of genes on the nuclear genome. Sex-specific mitochondrial genetic control of gene expression has been demonstrated in Drosophila melanogaster, where males were found to drive most of the total variation in gene expression. This has potential implications for male-related health and disease resultingdoi:10.1093/hmg/ddw347 pmid:27798101 pmcid:PMC6078603 fatcat:y4munu5renegrlhtk2wj6xfwmu
more »... variation in mtDNA solely inherited from the mother. We used a family-based study comprised of 47,323 gene expression probes and 78 mitochondrial SNPs (mtSNPs) from n = 846 individuals to examine the extent of mitochondrial genetic control of gene expression in humans. This identified 15 significant probe-mtSNP associations (P < 10 −8 ) corresponding to 5 unique genes on the mitochondrial and nuclear genomes, with three of these genes corresponding to mitochondrial genetic control of gene expression in the nuclear genome. The associated mtSNPs for three genes (one cis and two trans associations) were replicated (P < 0.05) in an independent dataset of n = 452 unrelated individuals. There was no evidence for sexual dimorphic gene expression in any of these five probes. Sex-specific effects were examined by applying our analysis to males and females separately and testing for differences in effect size. The MEST gene was identified as having the most significantly different effect sizes across the sexes (P ≈ 10 −7 ). MEST was similarly expressed in males and females with the G allele; however, males with the C allele are highly expressed for MEST, while females show no expression of the gene. This study provides evidence for the mitochondrial genetic control of expression of several genes in humans, with little evidence found for sex-specific effects.
Despite the important role DNA methylation plays in transcriptional regulation, the transgenerational inheritance of DNA methylation is not well understood. The genetic heritability of DNA methylation has been estimated using twin pairs, although concern has been expressed whether the underlying assumption of equal common environmental effects are applicable due to intrauterine differences between monozygotic and dizygotic twins. We estimate the heritability of DNA methylation on peripheraldoi:10.1186/gb-2014-15-5-r73 pmid:24887635 pmcid:PMC4072933 fatcat:kfc2hsyrjvgmfftf3s44relria
more »... d leukocytes using Illumina HumanMethylation450 array using a family based sample of 614 people from 117 families, allowing comparison both within and across generations. Results: The correlations from the various available relative pairs indicate that on average the similarity in DNA methylation between relatives is predominantly due to genetic effects with any common environmental or zygotic effects being limited. The average heritability of DNA methylation measured at probes with no known SNPs is estimated as 0.187. The ten most heritable methylation probes were investigated with a genome-wide association study, all showing highly statistically significant cis mQTLs. Further investigation of one of these cis mQTL, found in the MHC region of chromosome 6, showed the most significantly associated SNP was also associated with over 200 other DNA methylation probes in this region and the gene expression level of 9 genes.
Postpartum depression (PPD) is one of the most frequent complications of childbirth and particularly is suited to genetic investigation as it is more homogenous than major depression outside of the perinatal period. We developed an iOS app (PPD ACT) to recruit, consent, screen, and enable DNA collection from women with a lifetime history of PPD to sufficiently power genome-wide association studies. In 1 year, we recruited 7344 women with a history of PPD and have biobanked 2946 DNA samples fromdoi:10.1038/s41398-018-0305-5 pmid:30498212 pmcid:PMC6265256 fatcat:waznzevcczbj5it6odb7xaki5m
more »... the US. This sample of PPD cases was notably severely affected and within 2 years of their worst episode of PPD. Clinical validation was performed within a hospital setting on a subset of participants and recall validity assessed 6-9 months after initial assessment to ensure reliability of screening tools. Here we detail the creation of the PPD ACT mobile app including design, ethical, security, and deployment considerations. We emphasize the importance of multidisciplinary collaboration to correctly implement such a research project. Additionally, we describe our ability to customize the PPD ACT platform to deploy internationally in order to collect a global sample of women with PPD.
DNA methylation plays an important role in the regulation of transcription. Genetic control of DNA methylation is thus a potential candidate for explaining the many identified SNP associations with diseases and complex traits that are not found in coding regions. We identified and replicated 52,916 cis and 2,025 trans DNA methylation quantitative trait loci (mQTL) using methylation measured on Illumina HumanMethylation450 arrays in the Brisbane Systems Genetics Study (n=614 from 177 families)doi:10.1101/166710 fatcat:diof2i5y6vfdxjspbmb5ibg5r4
more »... d the Lothian Birth Cohorts of 1921 and 1936 (combined n = 1366). The trans mQTL SNPs were found to be over-represented in the subtelomeric 1Mbp of the genome and on chromosomes 16 and 19. There was a significant increase in trans mQTL DNA methylation sites in upstream and 5' UTR regions. No association was observed between either the SNPs or DNA methylation sites of trans mQTL and telomere length. LD Score regression was used to partition the heritability for a number of complex traits and diseases into components due to mQTL and the remainder of the genome. Significant enrichment was observed for height (p = 2.1x10^-10), ulcerative colitis (p = 2x10^-5), Crohn's disease (p = 6x10^-8) and coronary artery disease (p = 5.5x10^-6) when compared to a random sample of SNPs with matched minor allele frequency. This enrichment is explained by the genomic location of the mQTL SNPs, which are biased towards genic regions of the genome due to the combination of the vast majority being located in cis to the DNA methylation probes and the probes on the array being over-representing genic regions.
Traditionally twins are classiWed as dizygous or fraternal and monozygous or identical (Hall Twinning, 362, 2003 and 735-743). We report a rare case of 46,XX/46,XY twins: Twin A presented with ambiguous genitalia and Twin B was a phenotypically normal male. These twins demonstrate a third, previously unreported mechanism for twinning. The twins underwent initial investigation with 17-hydroxyprogesterone and testosterone levels, pelvic ultrasound and diagnostic laparoscopy. Cytogenetic analysisdoi:10.1007/s00439-006-0279-x pmid:17165045 fatcat:lnlbusojqvdzjk6skuh4iyxrie
more »... as performed on peripheral blood cells and skin Wbroblasts. Histological examination and Fluorescence in situ hybridization studies on touch imprints were performed on gonadal biopsies. DNA analysis using more than 6,000 DNA markers was performed on skin Wbroblast samples from the twins and on peripheral blood samples from both parents. Twin A was determined to be a true hermaphrodite and Twin B an apparently normal male. Both twins had a 46,XX/46,XY chromosome complement in peripheral lymphocytes, skin Wbroblasts, and gonadal biopsies. The proportion of XX to XY cells varied between the twins and the tissues evaluated. Most signiWcantly the twins shared 100% of maternal alleles and approximately 50% of paternal alleles in DNA analysis of skin Wbroblasts. The twins are chimeric and share a single genetic contribution from their mother but have two genetic contributions from their father thus supporting the existence of a third, previously unreported type of twinning.
K Henders, Rico Lee, Ashleigh Lin, Patrick McGorry, Simon Rice, Lianne Schmaal and Stephen J Wood in Australian & New Zealand Journal of Psychiatry ... material, SuppMaterial for Harmonised collection of data in youth mental health: Towards large datasets by Suzie Lavoie, Kelly Allott, Paul Amminger, Cali Bartholomeusz, Maximus Berger, Michael Breakspear, Anjali ...doi:10.25384/sage.8011136.v1 fatcat:wav52hz7xvffngncmp4plxxv6i
The observed number of successes for each IndexSNP (k) out of the total count of IndexSNPs (n) was then modelled as . ... Here, we are using family based pedigree information rather than SNP based IBD to account for relationships between individuals and so ϕ jk is the kinship coefficient between individuals j and k. ...doi:10.1038/nature13005 pmid:24572353 pmcid:PMC3984375 fatcat:eyw2j6n23zbeblqjn4vgiud4vu
The Prevalence and persistence of ADHD have not been described in young Australian adults and few studies have examined how conduct problems (CP) are associated with ADHD for this age group. We estimate lifetime and adult prevalence and persistence rates for three categories of ADHD for 3795 Australian adults, and indicate how career, health and childhood risk factors differ for people with ADHD symptoms and ADHD symptoms plus CP. Trained interviewers collected participant experience of ADHD,doi:10.1371/journal.pone.0047404 pmid:23071800 pmcid:PMC3468512 fatcat:rc3cj5kbbfbdtgsgcx5zzdpcua
more »... , education, employment, childhood experience, relationship and health variables. Three diagnostic definitions of ADHD used were (i) full DSM-IV criteria; (ii) excluding the age 7 onset criterion (no age criterion); (iii) participant experienced difficulties due to ADHD symptoms (problem symptoms). Prevalence rates in adulthood were 1.1%, 2.3% and 2.7% for each categorization respectively. Persistence of ADHD from childhood averaged across gender was 55.3% for full criteria, 50.3% with no age criterion and 40.2% for problem symptoms. ADHD symptoms were associated with parental conflict, poor health, being sexually assaulted during childhood, lower education, income loss and higher unemployment. The lifetime prevalence of conduct problems for adults with ADHD was 57.8% and 6.9% for adults without ADHD. The greatest disadvantage was experienced by participants with ADHD plus CP. The persistence of ADHD into adulthood was greatest for participants meeting full diagnostic criteria and inattention was associated with the greatest loss of income and disadvantage. The disadvantage associated with conduct problems differed in severity and was relevant for a high proportion of adults with ADHD. Women but not men with ADHD reported more childhood adversity, possibly indicating varied etiology and treatment needs. The impact and treatment needs of adults with ADHD and CP and the report of sexual assault during childhood by women and men with ADHD also deserve further study.
Here we have presented results of an eQTL study involving ,18 k probes, each tested against .500 k SNPs. ... The variable m represents the mean expression level across all individuals and C j and P k are random effects removing variation in the data due to chip j and chip position k respectively, and e ijk is ...doi:10.1371/journal.pone.0035430 pmid:22563384 pmcid:PMC3338511 fatcat:vqeolekyercfrkphsr2vlmijxa
Context: The genetic contribution to liability for opioid dependence is well established; identification of the responsible genes has proved challenging. Objective: To examine association of 1430 candidate gene single-nucleotide polymorphisms (SNPs) with heroin dependence, reporting here only the 71 SNPs in the chromosome 11 gene cluster (NCAM1, TTC12, ANKK1, DRD2) that include the strongest observed associations. Design: Case-control genetic association study that included 2 control groupsdoi:10.1001/jamapsychiatry.2013.282 pmid:23303482 pmcid:PMC3789525 fatcat:xu7bdmsmajat7ptjuetybelmrm
more »... king an established optimal control group). Setting: Semistructured psychiatric interviews. Participants: A total of 1459 Australian cases ascertained from opioid replacement therapy clinics, 531 neighborhood controls ascertained from economically disadvantaged areas near opioid replacement therapy clinics, and 1495 unrelated Australian Twin Registry controls not dependent on alcohol or illicit drugs selected from a twin and family sample. Main Outcome Measure: Lifetime heroin dependence. Results: Comparison of cases with Australian Twin Registry controls found minimal evidence of association for all chromosome 11 cluster SNPs (PՆ.01); a similar comparison with neighborhood controls revealed greater differences (PՆ1.8ϫ10 Ϫ4 ). Comparing cases (n=1459) with the subgroup of neighborhood controls not dependent on illicit drugs (n=340), 3 SNPs were significantly associated (correcting for multiple testing): ANKK1 SNP rs877138 (most strongly associated; odds ratio=1.59; 95% CI, 1.32-1.92; P=9.7ϫ10 Ϫ7 ), ANKK1 SNP rs4938013, and TTC12 SNP rs7130431. A similar pattern of association was observed when comparing illicit drug-dependent (n=191) and nondependent (n=340) neighborhood controls, suggesting that liability likely extends to nonopioid illicit drug dependence. Aggregate heroin dependence risk associated with 2 SNPs, rs877138 and rs4492854 (located in NCAM1), varied more than 4-fold (P=2.7ϫ 10 Ϫ9 for the risk-associated linear trend). Conclusions: Our results provide further evidence of association for chromosome 11 gene cluster SNPs with substance dependence, including extension of liability to illicit drug dependence. Our findings highlight the necessity of considering drug exposure history when selecting control groups for genetic investigations of illicit drug dependence.
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