Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans.

The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerström Test for Nicotine Dependence score⩾4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)⩾0.05), aggregate low frequency variants (0.05>MAF⩾0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 × coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 × 10(-11); African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking-related diseases such as lung cancer.

Somatic, positive and negative domains of the Center for Epidemiological Studies Depression (CES-D) scale: a meta-analysis of genome-wide association studies.

BACKGROUND: Major depressive disorder (MDD) is moderately heritable, however genome-wide association studies (GWAS) for MDD, as well as for related continuous outcomes, have not shown consistent results. Attempts to elucidate the genetic basis of MDD may be hindered by heterogeneity in diagnosis. The Center for Epidemiological Studies Depression (CES-D) scale provides a widely used tool for measuring depressive symptoms clustered in four different domains which can be combined together into a total score but also can be analysed as separate symptom domains. METHOD: We performed a meta-analysis of GWAS of the CES-D symptom clusters. We recruited 12 cohorts with the 20- or 10-item CES-D scale (32 528 persons). RESULTS: One single nucleotide polymorphism (SNP), rs713224, located near the brain-expressed melatonin receptor (MTNR1A) gene, was associated with the somatic complaints domain of depression symptoms, with borderline genome-wide significance (p discovery = 3.82 × 10-8). The SNP was analysed in an additional five cohorts comprising the replication sample (6813 persons). However, the association was not consistent among the replication sample (p discovery+replication = 1.10 × 10-6) with evidence of heterogeneity. CONCLUSIONS: Despite the effort to harmonize the phenotypes across cohorts and participants, our study is still underpowered to detect consistent association for depression, even by means of symptom classification. On the contrary, the SNP-based heritability and co-heritability estimation results suggest that a very minor part of the variation could be captured by GWAS, explaining the reason of sparse findings.

Novel DNA methylation signatures of tobacco smoking with trans-ethnic effects.

BACKGROUND: Smoking remains one of the leading preventable causes of death. Smoking leaves a strong signature on the blood methylome as shown in multiple studies using the Infinium HumanMethylation450 BeadChip. Here, we explore novel blood methylation smoking signals on the Illumina MethylationEPIC BeadChip (EPIC) array, which also targets novel CpG-sites in enhancers. METHOD: A smoking-methylation meta-analysis was carried out using EPIC DNA methylation profiles in 1407 blood samples from four UK population-based cohorts, including the MRC National Survey for Health and Development (NSHD) or 1946 British birth cohort, the National Child Development Study (NCDS) or 1958 birth cohort, the 1970 British Cohort Study (BCS70), and the TwinsUK cohort (TwinsUK). The overall discovery sample included 269 current, 497 former, and 643 never smokers. Replication was pursued in 3425 trans-ethnic samples, including 2325 American Indian individuals participating in the Strong Heart Study (SHS) in 1989-1991 and 1100 African-American participants in the Genetic Epidemiology Network of Arteriopathy Study (GENOA). RESULTS: Altogether 952 CpG-sites in 500 genes were differentially methylated between smokers and never smokers after Bonferroni correction. There were 526 novel smoking-associated CpG-sites only profiled by the EPIC array, of which 486 (92%) replicated in a meta-analysis of the American Indian and African-American samples. Novel CpG sites mapped both to genes containing previously identified smoking-methylation signals and to 80 novel genes not previously linked to smoking, with the strongest novel signal in SLAMF7. Comparison of former versus never smokers identified that 37 of these sites were persistently differentially methylated after cessation, where 16 represented novel signals only profiled by the EPIC array. We observed a depletion of smoking-associated signals in CpG islands and an enrichment in enhancer regions, consistent with previous results. CONCLUSION: This study identified novel smoking-associated signals as possible biomarkers of exposure to smoking and may help improve our understanding of smoking-related disease risk.

'Born in Michigan? You're in the biobank': engaging population biobank participants through Facebook advertisements.

BACKGROUND/AIMS: Despite a broad call for biobanks to use social media, data is lacking regarding the capacity of social media tools, especially advertising, to engage large populations on this topic. METHODS: We used Facebook advertising to engage Michigan residents about the BioTrust for Health. We conducted a low-budget (

Considerations for designing a prototype genetic test for use in translational research.

BACKGROUND: Translational research is needed to explore how people will respond to personal genetic susceptibility information related to common health conditions. Maximizing the rigor of this research will require that genetic test results be returned to study participants. Currently, there is no established method that guides the selection of genetic variants to be used in research with these objectives. METHODS AND RESULTS: To address this question, we designed a process to identify gene variants and health conditions to be included in a prototype genetic test for use in a larger research effort, the Multiplex Initiative. The intention of this exploration was to facilitate research that generates individual genetic test results that are returned to study participants. Inclusion criteria were developed as part of a transdisciplinary and iterative process that considered the weight of evidential support for genetic association with common health conditions, the appropriateness of use in human subjects research, and the recommendations of expert peer reviewers. CONCLUSIONS: The selection process was designed to identify gene variants for the limited purpose of translational research and, therefore, should not be seen as producing a valid clinical test. However, this example of an applied selection process may provide guidance for researchers who are designing studies to evaluate the implications of genetic susceptibility testing through the return of personalized genetic information. As the rate of genomic discoveries increases, such research will be essential in steering the translation of this information towards the greatest public health benefit.

Understandings of basic genetics in the United States: results from a national survey of black and white men and women.

AIM: This study examined understandings of basic genetic concepts among Americans. METHOD: In a national telephone survey of 1,200 Americans with equal representation among Black and White men and women, subjects responded to 8 items developed by a multidisciplinary team of experts that assessed understanding of basic concepts in multiple domains, including inheritance, genetics and race, and genetics and behavior. RESULTS: Over 70% of subjects responded correctly on items about the genetic similarity of identical twins and siblings. Less than half of subjects responded correctly on all other items. Understanding of genetics was lowest in three areas: types/locations of genes in the body (29% correct), a genetic basis for race (25% correct), and the influence of single genes on behaviors (24% correct). Logistic regression models controlling for age and education showed some differences by race and gender on specific items but also showed that understandings are generally similar across these groups. CONCLUSION: Misunderstandings about genetics are common among Black and White American men and women. Responses appear to reflect personal experiences, group values and interests. These findings emphasize the need for initiatives to improve the public's genetic literacy as well as a need for further investigation in this domain.

Combinations of glutathione S-transferase genotypes and risk of early-onset lung cancer in Caucasians and African Americans: a population-based study.

Polymorphisms in GSTM1, GSTT1 and GSTP1 genes in humans are associated with the reduction of enzymatic activity toward several substrates, including those in tobacco smoke. To investigate the potential role these polymorphisms have, as modulators of early-onset lung cancer risk, a population-based case-control study involving early-onset lung cancer cases was performed. Biological samples were available for 350 individuals diagnosed <50 years of age identified from the metropolitan Detroit Surveillance, Epidemiology and End Results (SEER) program and 410 cases of age, race and sex-matched controls ascertained through random digit dialing. African Americans carrying at least one G allele at the GSTP1 locus were 2.9-fold more likely to have lung cancer compared with African Americans without a G allele after adjustment for age, sex, pack years of smoking and history of lung cancer in a first-degree relative (95% CI 1.29-6.20). African Americans with either one or two risk genotypes at the GSTM1 and GSTP1 loci were at increased risk of having lung cancer compared with those having fully functional GSTM1 and GSTP1 genes (OR = 2.8, 95% CI 1.1-7.2 and OR = 4.0, 95% CI 1.3-12.2, respectively). No significant single gene associations between GSTM1, GSTT1 or GSTP1 and early-onset lung cancer were identified in Caucasians, after adjusting for age, sex, pack years and family history of lung cancer. However, our results suggest that specific combinations of glutathione S-transferase polymorphisms increase the risk of early-onset of lung cancer. Joint analysis of these genotypes may identify individuals who are at a higher risk of developing early-onset lung cancer with a greater certainty than single gene studies.

Linkage analysis of plasma ApoE in three ethnic groups: multiple genes with context-dependent effects.

We performed variance component-based linkage analysis in four samples (two of non-Hispanic European-Americans from Rochester, MN; African-Americans from Jackson, MS; and Mexican-Americans from Starr County, TX) to identify chromosomal regions containing genes influencing plasma apolipoprotein E (apoE) levels. The APOE gene region on chromosome (chr) 19 was identified with a LOD > or = 2.00 in both samples from Rochester and the sample from Jackson. Adjustment of apoE levels for differences among means of genotypes defined by the APOE epsilon2/3/4 alleles reduced evidence of linkage, indicating that the APOE gene was responsible for the majority of the linkage signal. In stratified linkage analyses, there was a LOD of 1.70 in the Starr County sibships with average total cholesterol (TC) above the median level for all sibships in that population. Adjustment for APOE genotype did not remove this LOD score, suggesting a second gene in this region may influence apoE variation. Evidence of linkage (LOD= 3.32) on chr 17 was observed in the Starr County sibships with average TC below the median. Inter-individual variation in plasma apoE level may be influenced by variations in the structural gene, and at least one other gene whose effects differ among populations and are dependent on the influence of unmeasured genetic and environmental factors indexed by correlated measures of lipid metabolism.