Biology subjects

Markunas, C. A.

Publications and source records attributed to Markunas, C. A..

4 recordsLinked to original sources

bioRxiv2020

Expanding the Genetic Architecture of Nicotine Dependence and its Shared Genetics with Multiple Traits: Findings from the Nicotine Dependence GenOmics (iNDiGO) Consortium

Cigarette smoking is the leading cause of preventable morbidity and mortality. Knowledge is evolving on genetics underlying initiation, regular smoking, nicotine dependence (ND), and cessation. We performed a genome-wide association study using the Fagerstrom Test for ND (FTND) in 58,000 smokers of European or African ancestry. Five genome-wide significant loci, including two novel loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416) were identified, and loci reported for other smoking traits were extended to ND. Using the heaviness of smoking index (HSI) in the UK Biobank (N=33,791), rs2714700 was consistently associated, but rs1862416 was not associated, likely reflecting ND features not captured by the HSI. Both variants were cis-eQTLs (rs2714700 for MAGI2-AS3 in hippocampus, rs1862416 for TENM2 in lung), and expression of genes spanning ND-associated variants was enriched in cerebellum. SNP-based heritability of ND was 8.6%, and ND was genetically correlated with 17 other smoking traits (rg=0.40-0.95) and co-morbidities. Our results emphasize the FTND as a composite phenotype that expands genetic knowledge of smoking, including loci specific to ND.

genomics↗

bioRxiv2019

Genome-wide DNA methylation differences in nucleus accumbens of smokers vs. nonsmokers

Numerous DNA methylation (DNAm) biomarkers of cigarette smoking have been identified in peripheral blood studies, but their relevance as neurobiological indicators is unknown due to DNAm tissue-specificity. In contrast, blood-based studies may not detect brain-specific smoking-related DNAm differences that may provide greater insight into the neurobiology of smoking behaviors. We report the first epigenome-wide association study (EWAS) of smoking in human postmortem brain, focusing on nucleus accumbens (NAc) as a key brain region in developing addiction. Following Illumina HumanMethylation EPIC array data generation and quality control, 221 decedents (120 European American [23% current smokers], 101 African American [26% current smokers]) were analyzed. DNAm by smoking (current vs. nonsmoking) was tested using robust linear regression models adjusted for age, sex, cell-type proportion, DNAm-derived negative control principal components (PCs), and genotype-derived PCs. Separate ancestry-specific results were combined via meta-analysis, resulting in 7 CpGs that exceeded false discovery rate (FDR)<0.05. Using published smoking EWAS results in blood, we extended our NAc findings to identify DNAm smoking effects that are unique (tissue-specific) versus shared between tissues (tissue-shared). Of the 7 CpGs identified in NAc, 3 CpGs were located near genes previously indicated with blood-based smoking DNAm biomarkers: ZIC1, ZCCHC24, and PRKDC. The other 4 CpGs are novel for smoking-related DNAm changes: ABLIM3, APCDD1L, MTMR6, and CTCF. Our results provide the first evidence for smoking-related DNAm changes in human NAc, highlighting CpGs that were previously undetected as peripheral biomarkers and may reflect brain-specific processes.

neuroscience↗

bioRxiv2019

Epigenome-wide analysis uncovers a blood-based DNA methylation biomarker of lifetime cannabis use.

Cannabis use is highly prevalent and is associated with adverse and beneficial effects. To better understand the full spectrum of health consequences, biomarkers that accurately classify cannabis use are needed. DNA methylation (DNAm) is an excellent candidate, yet no blood-based epigenome-wide association studies (EWAS) in humans exist. We conducted an EWAS of lifetime cannabis use (ever vs. never) using blood-based DNAm data from a case-cohort study within Sister Study, a prospective cohort of women at risk of developing breast cancer (Discovery N=1,730 [855 ever users]; Replication N=853 [392 ever users]). We identified and replicated an association with lifetime cannabis use at cg15973234 (CEMIP): combined P=3.3x10-8. We found no overlap between published blood-based cis-meQTLs of cg15973234 and reported lifetime cannabis use-associated SNPs (P<0.05), suggesting that the observed DNAm difference was driven by cannabis exposure. We also developed a multi-CpG classifier of lifetime cannabis use using penalized regression of top EWAS CpGs. The resulting 49-CpG classifier produced an area under the curve (AUC)=0.74 (95% confidence interval [0.72, 0.76], P=2.00x10-5) in the discovery sample and AUC=0.54 ([0.51, 0.57], P=4.64x10-2) in the replication sample. Our EWAS findings provide evidence that blood-based DNAm is associated with lifetime cannabis use.

genomics↗

bioRxiv2017

Developmental effects of maternal smoking during pregnancy on the human frontal cortex transcriptome

Cigarette smoking during pregnancy is a major public health concern. While there are well-described consequences in early child development, there is very little known about the effects of maternal smoking on human cortical biology during prenatal life. We therefore performed a genome-wide differential gene expression analysis using RNA sequencing (RNA-seq) on prenatal (N=33; 16 smoking-exposed) as well as adult (N=207; 57 active smokers) human post-mortem prefrontal cortices. Smoking exposure during the prenatal period was directly associated with differential expression of 14 genes; in contrast, during adulthood, despite a much larger sample size, only 2 genes showed significant differential expression (FDR<10%). Moreover, 1,315 genes showed significantly different exposure effects between maternal smoking during pregnancy and direct exposure in adulthood (FDR<10%) - these differences were largely driven by prenatal differences that were enriched for pathways previously implicated in addiction and synaptic function. Furthermore, prenatal and age-dependent differentially expressed genes were enriched for genes implicated in non-syndromic autism spectrum disorder (ASD) and were differentially expressed as a set between patients with ASD and controls in post-mortem cortical regions. These results underscore the enhanced sensitivity to the biological effect of smoking exposure in the developing brain and offer novel insight into the effects of maternal smoking during pregnancy on the prenatal human brain. They also begin to address the relationship between in utero exposure to smoking and the heightened risks for the subsequent development of neuropsychiatric disorders.\n\nOne Sentence SummaryMaternal smoking during pregnancy alters the expression of genes within the developing human cortex and these changes are enriched for genes implicated in neuropsychiatric disorders.

neuroscience↗