Linkage disequilibrium in young genetically isolated Dutch population

The design and feasibility of genetic studies of complex diseases are critically dependent on the extent and distribution of linkage disequilibrium (LD) across the genome and between different populations. We have examined genomewide and region-specific LD in a young genetically isolated population identified in the Netherlands by genotyping approximately 800 Short Tandem Repeat markers distributed genomewide across 58 individuals. Several regions were an

Views on and experiences of electronic cigarettes: a qualitative study of women who are pregnant or have recently given birth.

Background Electronic cigarettes (ECs) are increasingly used for reducing or stopping smoking, with some studies showing positive outcomes. However, little is known about views on ECs during pregnancy or postpartum and previous studies have nearly all been conducted in the US and have methodological limitations, such as not distinguishing between smokers and ex/non-smokers. A greater understanding of this topic will help to inform both clinicians and EC interventions. We elicited views and experiences of ECs among UK pregnant or recently pregnant women. Methods We conducted semi-structured telephone interviews, using topic guides, with pregnant or recently pregnant women, who were current or recent ex-smokers. To ensure broad views of ECs were obtained, recruitment was from several geographical locations and via various avenues of recruitment. This included stop smoking services, antenatal and health visitor clinics, a pregnancy website and an informal network. Participants were 15 pregnant and 15 postpartum women, including nine current EC users, 11 ex-users, and 10 never-users. Five women who were interviewed in pregnancy were later interviewed in postpartum to explore if their views had changed. Audio data was transcribed verbatim and framework analysis was applied. Results Five main themes emerged: motivations for use (e.g., for stopping or reducing smoking), social stigma (e.g., avoiding use in public, preferring ‘discrete’ NRT), using the EC (e.g., mostly used at home); consumer aspects (e.g., limited advice available), and harm perceptions (e.g., viewed as less harmful than smoking; concerns about safety and addiction). Conclusions ECs were viewed positively by some pregnant and postpartum women and seen as less harmful than smoking and useful as aids for reducing and stopping smoking. However, due to perceived social stigma, some women feel uncomfortable using ECs in public, especially during pregnancy, and had concerns about safety and nicotine dependence. Health professionals and designers of EC interventions need to provide women with up-to-date and consistent information and advice about safety and dependence, as well as considering the influence of social stigma

Associations of First Trimester Co-Use of Tobacco and Cannabis with Prenatal Immune Response and Psychosocial Well-Being

PURPOSE: This study aims to describe the association of first trimester co-use of tobacco and cannabis with maternal immune response and psychosocial well-being, relative to tobacco use only. METHODS: A preliminary midpoint analysis included 138 pregnant women with biologically verified tobacco use, 38 of whom (28%) also tested positive for recent cannabis use. Maternal perceived stress (Perceived Stress Scale), depressive symptoms (Edinburgh Postnatal Depression Scale), and serum immune markers (IL-1β, IL-2, IL-6, IL-8, IL-10, TNFα, CRP, MMP8), were collected, although cytokine data were only available for 122 women. RESULTS: Participant average age was 29.1 years, approximately half had a high school education or less, and half were unemployed. Compared to tobacco only users, co-users were more likely to be non-White, younger and more economically disadvantaged. In the adjusted linear regression models, TNF-α levels were significantly lower among co-users relative to tobacco only users, after adjusting for age, race/ethnicity, body mass index and tobacco use group (tobacco cigarettes, electronic nicotine delivery devices [ENDS] or both). TNF-α was the only immune marker found to be significant in this analysis. Measured stress levels (M = 5.9, SD = 3.3; potential range 0-16) and depression scores (M = 7.8, SD = 5.8; potential range 0-30) were low across all participants and did not differ as a function of co-use. CONCLUSION: Preliminary results suggest women co-using during the first trimester exhibit decreased pro-inflammatory immune responsivity on one out of eight markers. Further research is needed to determine the impact of this immune modulation on fetal health outcomes and the unique contribution of cannabis

Advertising Exposure and Use of E-Cigarettes Among Female Current and Former Tobacco Users of Childbearing Age

Objective: The study examined the relationship between exposure to e‐cigarette advertising and e‐cigarette use by pregnancy status, including use of flavored e‐cigarette products, among women of childbearing age. Design: A cross‐sectional, correlational design was used. Subjects: Female current or former tobacco users in Central and Eastern Kentucky, 18–45 years old (N = 194, 52% pregnant). Measures: Demographics, pregnancy status, cigarette and e‐cigarette use, and exposure to e‐cigarette advertising. Results: Younger age, white non‐Hispanic race, and greater exposure to e‐cigarette advertising were associated with a higher likelihood of ever using e‐cigarettes (p \u3c .05 for each variable). Pregnancy was not associated with ever use (p = .11). Younger age was associated with use of flavored e‐cigarettes (p = .0027). Among e‐cigarette users, those who used flavored products were more likely to have seen advertisements or information about e‐cigarettes on social media, compared to those who used unflavored e‐cigarettes only (p = .016). Conclusion: There is a link between advertising exposure and ever use of e‐cigarettes. Pregnancy status is not significantly associated with ever use. Use of flavored e‐cigarettes is associated with younger age. E‐cigarette users with greater exposure to advertising on social media were more likely to use flavored products

Evidence of gene-environment interaction for two genes on chromosome 4 and environmental tobacco smoke in controlling the risk of nonsyndromic cleft palate

Nonsyndromic cleft palate (CP) is one of the most common human birth defects and both genetic and environmental risk factors contribute to its etiology. We conducted a genome-wide association study (GWAS) using 550 CP case-parent trios ascertained in an international consortium. Stratified analysis among trios with different ancestries was performed to test for GxE interactions with common maternal exposures using conditional logistic regression models. While no single nucleotide polymorphism (SNP) achieved genome-wide significance when considered alone, markers in SLC2A9 and the neighboring WDR1 on chromosome 4p16.1 gave suggestive evidence of gene-environment interaction with environmental tobacco smoke (ETS) among 259 Asian trios when the models included a term for GxE interaction. Multiple SNPs in these two genes were associated with increased risk of nonsyndromic CP if the mother was exposed to ETS during the peri-conceptual period (3 months prior to conception through the first trimester). When maternal ETS was considered, fifteen of 135 SNPs mapping to SLC2A9 and 9 of 59 SNPs in WDR1 gave P values approaching genome-wide significance (10-6<P<10-4) in a test for GxETS interaction. SNPs rs3733585 and rs12508991 in SLC2A9 yielded P = 2.26×10-7 in a test for GxETS interaction. SNPs rs6820756 and rs7699512 in WDR1 also yielded P = 1.79×10-7 and P = 1.98×10-7 in a 1 df test for GxE interaction. Although further replication studies are critical to confirming these findings, these results illustrate how genetic associations for nonsyndromic CP can be missed if potential GxE interaction is not taken into account, and this study suggest SLC2A9 and WDR1 should be considered as candidate genes for CP. © 2014 Wu et al

Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals

IMPORTANCE: Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays. OBJECTIVE: To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals. DESIGN, SETTING, AND PARTICIPANTS: Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-based ROH measurements were analyzed using raw or imputed genotype data. We studied the raw genotypes from 2 case-control subsets grouped based on SNP array: Alzheimer's Disease Genetics Consortium data set (871 cases and 1620 control individuals) and Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals). We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals. MAIN OUTCOMES AND MEASURES: The ROHs larger than 1 Mb, 2 Mb, or 3 Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses. RESULTS: The African American cohort had a low degree of inbreeding (F ~ 0.006). In the Alzheimer's Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2 Mb (P = .004) or greater than 3 Mb (P = .02), as well as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 = .04; ROHs >2 Mb). In the Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 = .02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 = .03; ROHs >3 Mb). A total of 43 of 49 nominally significant genes common for both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs >1 Mb in cases vs 12.11 in controls; 2.986 Mb average size of ROHs >2 Mb in cases vs 2.889 Mb in controls; and 22% of cases with ROHs >3 Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2 = .006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 = .01; ROHs >1 Mb), encoding a protein from the Claudin family, members of which were previously suggested as AD biomarkers. CONCLUSIONS AND RELEVANCE: To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals

Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesOver the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR) <1.15).We conducted a large-scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls).We observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; P = 9 × 10(-6)). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as FOXP1 at 3p13, ATP2B2 at 3p25.3, and a 'neurodevelopmental hub' on chromosome 8p11.23.This study is an important step in the ongoing endeavour to identify the loci which underpin the common variant signal in ASD. In addition to novel GWS loci, we have identified a significant genetic correlation with schizophrenia and association of ASD with several neurodevelopmental-related genes such as EXT1, ASTN2, MACROD2, and HDAC4.National Institutes of Mental Health (NIMH, USA) ACE Network Autism Genetic Resource Exchange (AGRE) is a program of Autism Speaks (USA) The Autism Genome Project (AGP) from Autism Speaks (USA) Canadian Institutes of Health Research (CIHR), Genome Canada Health Research Board (Ireland) Hilibrand Foundation (USA) Medical Research Council (UK) National Institutes of Health (USA) Ontario Genomics Institute University of Toronto McLaughlin Centre Simons Foundation Johns Hopkins Autism Consortium of Boston NLM Family foundation National Institute of Health grants National Health Medical Research Council Scottish Rite Spunk Fund, Inc. Rebecca and Solomon Baker Fund APEX Foundation National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD) endowment fund of the Nancy Pritzker Laboratory (Stanford) Autism Society of America Janet M. Grace Pervasive Developmental Disorders Fund The Lundbeck Foundation universities and university hospitals of Aarhus and Copenhagen Stanley Foundation Centers for Disease Control and Prevention (CDC) Netherlands Scientific Organization Dutch Brain Foundation VU University Amsterdam Trinity Centre for High Performance Computing through Science Foundation Ireland Autism Genome Project (AGP) from Autism Speak

Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders

Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways

Accelerated epigenetic age at birth and child emotional and behavioural development in early childhood: a meta-analysis of four prospective cohort studies in ECHO

Background: ‘Epigenetic clocks’ have been developed to accurately predict chronologic gestational age and have been associated with child health outcomes in prior work. Methods: We meta-analysed results from four prospective U.S cohorts investigating the association between epigenetic age acceleration estimated using blood DNA methylation collected at birth and preschool age Childhood Behavior Checklist (CBCL) scores. Results: Epigenetic ageing was not significantly associated with CBCL total problem scores (β = 0.33, 95% CI: −0.95, 0.28) and DSM-oriented pervasive development problem scores (β = −0.23, 95% CI: −0.61, 0.15). No associations were observed for other DSM-oriented subscales. Conclusions: The meta-analysis results suggest that epigenetic gestational age acceleration is not associated with child emotional and behavioural functioning for preschool age group. These findings may relate to our study population, which includes two cohorts enriched for ASD and one preterm birth cohort.; future work should address the role of epigenetic age in child health in other study populations

Autism-Associated DNA Methylation at Birth From Multiple Tissues Is Enriched for Autism Genes in the Early Autism Risk Longitudinal Investigation

Background: Pregnancy measures of DNA methylation, an epigenetic mark, may be associated with autism spectrum disorder (ASD) development in children. Few ASD studies have considered prospective designs with DNA methylation measured in multiple tissues and tested overlap with ASD genetic risk loci. Objectives: To estimate associations between DNA methylation in maternal blood, cord blood, and placenta and later diagnosis of ASD, and to evaluate enrichment of ASD-associated DNA methylation for known ASD-associated genes. Methods: In the Early Autism Risk Longitudinal Investigation (EARLI), an ASD-enriched risk birth cohort, genome-scale maternal blood (early n = 140 and late n = 75 pregnancy), infant cord blood (n = 133), and placenta (maternal n = 106 and fetal n = 107 compartments) DNA methylation was assessed on the Illumina 450k HumanMethylation array and compared to ASD diagnosis at 36 months of age. Differences in site-specific and global methylation were tested with ASD, as well as enrichment of single site associations for ASD risk genes (n = 881) from the Simons Foundation Autism Research Initiative (SFARI) database. Results: No individual DNA methylation site was associated with ASD at genome-wide significance, however, individual DNA methylation sites nominally associated with ASD (P &lt; 0.05) in each tissue were highly enriched for SFARI genes (cord blood P = 7.9 × 10-29, maternal blood early pregnancy P = 6.1 × 10-27, maternal blood late pregnancy P = 2.8 × 10-16, maternal placenta P = 5.6 × 10-15, fetal placenta P = 1.3 × 10-20). DNA methylation sites nominally associated with ASD across all five tissues overlapped at 144 (29.5%) SFARI genes. Conclusion: DNA methylation sites nominally associated with later ASD diagnosis in multiple tissues were enriched for ASD risk genes. Our multi-tissue study demonstrates the utility of examining DNA methylation prior to ASD diagnosis