Neonatal abstinence syndrome (NAS) due to in-utero opioid exposure is a growing epidemic with significant variability in clinical presentation and severity. Currently, NAS severity cannot be ...predicted based on clinical factors alone. To date, small studies have identified genetic variants in opioid receptor and stress response genes that are associated with differences in NAS pharmacologic treatment rates and length of hospitalization. In addition, epigenetic variation in the mu opioid receptor (OPRM1) gene has been associated with differences in NAS hospitalization outcomes. Examination of maternal genetic and epigenetic profiles may assist in prediction of NAS severity. Large-scale genomic studies are needed to elucidate the genetic architecture of and epigenetic modification related to NAS in order to develop more tailored personalized treatments for NAS.
Background Atopy and plasma IgE concentration are genetically complex traits, and the specific genetic risk factors that lead to IgE dysregulation and clinical atopy are an area of active ...investigation. Objective We sought to ascertain the genetic risk factors that lead to IgE dysregulation. Methods A genome-wide association study (GWAS) was performed in 6819 participants from the Framingham Heart Study (FHS). Seventy of the top single nucleotide polymorphisms (SNPs) were selected based on P values and linkage disequilibrium among neighboring SNPs and evaluated in a meta-analysis with 5 independent populations from the Cooperative Health Research in the Region of Augsburg cohort, the British 1958 Birth Cohort, and the Childhood Asthma Management Program cohort. Results Thirteen SNPs located in the region of 3 genes, FCER1A , signal transducer and activator of transcription 6 (STAT6) , and IL13 , were found to have genome-wide significance in the FHS cohort GWAS. The most significant SNPs from the 3 regions were rs2251746 ( FCER1A , P = 2.11 × 10−12 ), rs1059513 ( STAT6 , P = 2.87 × 10−8 ), and rs1295686 ( IL13 , P = 3.55 × 10−8 ). Four additional gene regions, HLA-G , HLA-DQA2 , HLA-A , and Duffy blood group, chemokine receptor (DARC) , reached genome-wide statistical significance in a meta-analysis combining the FHS and replication cohorts, although the DARC association did not appear independent of SNPs in the nearby FCER1A gene. Conclusion This GWAS of the FHS cohort has identified genetic loci in HLA genes that might have a role in the pathogenesis of IgE dysregulation and atopy. It also confirmed the association of the known susceptibility loci FCER1A , STAT6 , and IL13 for the dysregulation of total IgE.
Despite a significant genetic contribution to alcohol dependence (AD), few AD-risk genes have been identified to date. In the current study, we aimed to integrate genome-wide association studies ...(GWASs) and human protein interaction networks to investigate whether a subnetwork of genes whose protein products interact with one another might collectively contribute to AD. By using two discovery GWAS data sets of the Study of Addiction: Genetics and Environment (SAGE) and the Collaborative Study on the Genetics of Alcoholism (COGA), we identified a subnetwork of 39 genes that not only was enriched for genes associated with AD, but also collectively associated with AD in both European Americans (p < 0.0001) and African Americans (p = 0.0008). We replicated the association of the gene subnetwork with AD in three independent samples, including two samples of European descent (p = 0.001 and p = 0.006) and one sample of African descent (p = 0.0069). To evaluate whether the significant associations are likely to be false-positive findings and to ascertain their specificity, we examined the same gene subnetwork in three other human complex disorders (bipolar disorder, major depressive disorder, and type 2 diabetes) and found no significant associations. Functional enrichment analysis revealed that the gene subnetwork was enriched for genes involved in cation transport, synaptic transmission, and transmission of nerve impulses, all of which are biologically meaningful processes that may underlie the risk for AD. In conclusion, we identified a gene subnetwork underlying AD that is biologically meaningful and highly reproducible, providing important clues for future research into AD etiology and treatment.
Quantifying cell-type abundance in bulk tissue RNA-sequencing enables researchers to better understand complex systems. Newer deconvolution methodologies, such as MuSiC, use cell-type signatures ...derived from single-cell RNA-sequencing (scRNA-seq) data to make these calculations. Single-nuclei RNA-sequencing (snRNA-seq) reference data can be used instead of scRNA-seq data for tissues such as human brain where single-cell data are difficult to obtain, but accuracy suffers due to sequencing differences between the technologies. We propose a modification to MuSiC entitled 'DeTREM' which compensates for sequencing differences between the cell-type signature and bulk RNA-seq datasets in order to better predict cell-type fractions. We show DeTREM to be more accurate than MuSiC in simulated and real human brain bulk RNA-sequencing datasets with various cell-type abundance estimates. We also compare DeTREM to SCDC and CIBERSORTx, two recent deconvolution methods that use scRNA-seq cell-type signatures. We find that they perform well in simulated data but produce less accurate results than DeTREM when used to deconvolute human brain data. DeTREM improves the deconvolution accuracy of MuSiC and outperforms other deconvolution methods when applied to snRNA-seq data. DeTREM enables accurate cell-type deconvolution in situations where scRNA-seq data are not available. This modification improves characterization cell-type specific effects in brain tissue and identification of cell-type abundance differences under various conditions.
Black/African American (AA) individuals have a higher risk of Alzheimer's disease (AD) than White non-Hispanic persons of European ancestry (EUR) for reasons that may include economic disparities, ...cardiovascular health, quality of education, and biases in the methods used to diagnose AD. AD is also heritable, and some of the differences in risk may be due to genetics. Many AD-associated variants have been identified by candidate gene studies, genome-wide association studies (GWAS), and genome-sequencing studies. However, most of these studies have been performed using EUR cohorts. In this paper, we review the genetics of AD and AD-related traits in AA individuals. Importantly, studies of genetic risk factors in AA cohorts can elucidate the molecular mechanisms underlying AD risk in AA and other populations. In fact, such studies are essential to enable reliable precision medicine approaches in persons with considerable African ancestry. Furthermore, genetic studies of AA cohorts allow exploration of the ways the impact of genes can vary by ancestry, culture, and economic and environmental disparities. They have yielded important gains in our knowledge of AD genetics, and increasing AA individual representation within genetic studies should remain a priority for inclusive genetic study design.
Genetic associations for endophenotypes of Alzheimer's disease (AD) in cognitive stages preceding AD have not been thoroughly evaluated.
We conducted genome-wide association studies for AD-related ...endophenotypes including hippocampal volume, logical memory scores, and cerebrospinal fluid Aβ42 and total/phosphorylated tau in cognitively normal (CN), mild cognitive impairment, and AD dementia subjects from the Alzheimer's Disease Neuroimaging Initiative study.
In CN subjects, study-wide significant (P < 8.3 × 10−9) loci were identified for total tau near SRRM4 and C14orf79 and for hippocampal volume near MTUS1. In mild cognitive impairment subjects, study-wide significant association was found with single nucleotide polymorphisms (SNPs) near ZNF804B for logical memory test of delayed recall scores. We found consistent expression patterns of C14orf40 and MTUS1 in carriers with risk alleles of expression SNPs and in brains of AD patients, compared with in the noncarriers and in brains of controls.
Our findings for AD-related brain changes before AD provide insight about early AD-related biological processes.
•Genetic factors for Alzheimer's disease (AD)–related endophenotypes influencing prediagnosis stages are evaluated•Genetic factors affecting early changes for AD via expression are proposed.•Co-expression network study revealed that genes identified in this study are interconnected with known AD genes.•Genes and pathways in early biological processes in AD are enriched in neuronal or synaptic function.
Apolipoprotein E (APOE)*2 and APOE*4 are, respectively, the strongest protective and risk-increasing, common genetic variants for late-onset Alzheimer disease (AD), making APOE status highly relevant ...toward clinical trial design and AD research broadly. The associations of APOE genotypes with AD are modulated by age, sex, race and ethnicity, and ancestry, but these associations remain unclear, particularly among racial and ethnic groups understudied in the AD and genetics research fields.
To assess the stratified associations of APOE genotypes with AD risk across sex, age, race and ethnicity, and global population ancestry.
This genetic association study included case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Data were analyzed between March 2022 and April 2023. Genetic data were available from high-density, single-nucleotide variant microarrays, exome microarrays, and whole-exome and whole-genome sequencing. Summary statistics were ascertained from published AD genetic studies.
The main outcomes were risk for AD (odds ratios ORs) and risk of conversion to AD (hazard ratios HRs), with 95% CIs. Risk for AD was evaluated through case-control logistic regression analyses. Risk of conversion to AD was evaluated through Cox proportional hazards regression survival analyses.
Among 68 756 unique individuals, analyses included 21 852 East Asian (demographic data not available), 5738 Hispanic (68.2% female; mean SD age, 75.4 8.8 years), 7145 non-Hispanic Black (hereafter referred to as Black) (70.8% female; mean SD age, 78.4 8.2 years), and 34 021 non-Hispanic White (hereafter referred to as White) (59.3% female; mean SD age, 77.0 9.1 years) individuals. There was a general, stepwise pattern of ORs for APOE*4 genotypes and AD risk across race and ethnicity groups. Odds ratios for APOE*34 and AD risk attenuated following East Asian (OR, 4.54; 95% CI, 3.99-5.17),White (OR, 3.46; 95% CI, 3.27-3.65), Black (OR, 2.18; 95% CI, 1.90-2.49) and Hispanic (OR, 1.90; 95% CI, 1.65-2.18) individuals. Similarly, ORs for APOE*22+23 and AD risk attenuated following White (OR, 0.53, 95% CI, 0.48-0.58), Black (OR, 0.69, 95% CI, 0.57-0.84), and Hispanic (OR, 0.89; 95% CI, 0.72-1.10) individuals, with no association for Hispanic individuals. Deviating from the global pattern of ORs, APOE*22+23 was not associated with AD risk in East Asian individuals (OR, 0.97; 95% CI, 0.77-1.23). Global population ancestry could not explain why Hispanic individuals showed APOE associations with less pronounced AD risk compared with Black and White individuals. Within Black individuals, decreased global African ancestry or increased global European ancestry showed a pattern of APOE*4 dosage associated with increasing AD risk, but no such pattern was apparent for APOE*2 dosage with AD risk. The sex-by-age-specific interaction effect of APOE*34 among White individuals (higher risk in women) was reproduced but shifted to ages 60 to 70 years (OR, 1.48; 95% CI, 1.10-2.01) and was additionally replicated in a meta-analysis of Black individuals and Hispanic individuals (OR, 1.72; 95% CI, 1.01-2.94).
Through recent advances in AD-related genetic cohorts, this study provided the largest-to-date overview of the association of APOE with AD risk across age, sex, race and ethnicity, and population ancestry. These novel insights are critical to guide AD clinical trial design and research.
Abstract Background We report a genome-wide association study (GWAS) of nicotine dependence defined on the basis of scores on the Fagerström Test for Nicotine Dependence in European-American (EA) and ...African-American (AA) populations. Methods Our sample, from the one used in our previous GWAS, included only subjects who had smoked >100 cigarettes lifetime (2114 EA and 2602 AA subjects) and an additional 927 AA and 2003 EA subjects from the Study of Addiction: Genetics and Environment project via the database of Genotypes and Phenotypes (dbGAP). GWAS analysis considered Fagerström Test for Nicotine Dependence score as an ordinal trait, separately in each population and sample and by combining the results in meta-analysis. We also conducted analyses that were adjusted for other substance use disorder criteria in a single nucleotide polymorphism (SNP) subset. Results In EAs, one chromosome 7 intergenic region was genome-wide significant (GWS): rs13225753, p = 3.48 × 10−8 (adjusted). In AAs, GWS associations were observed at numerous SNPs mapped to a region on chromosome 14 of >305,000 base pairs (minimal p = 4.74 × 10−10 ). Two chromosome 8 regions were associated: p = 4.45 × 10−8 at DLC1 SNP rs289519 (unadjusted) and p = 1.10 × 10−9 at rs6996964 (adjusted for other substances), located between CSGALNACT1 and INTS10 . No GWS associations were observed at the chromosome 15 nicotinic receptor gene cluster ( CHRNA5-CHRNA3-CHRNB4 ) previously associated with nicotine dependence and smoking quantity traits. TSNAX - DISC1 SNP rs821722 ( p = 1.46 × 10−7 ) was the most significant result with substantial contributions from both populations; we previously identified DISC1 associations with opioid dependence. Pathway analysis identified association with nitric oxide synthase and adenosine monophosphate-activated protein kinase pathways in EAs. Conclusions The key risk loci identified, which require replication, offer novel insights into nicotine dependence biology.
We have identified a rare coding mutation, T835M (rs137875858), in the UNC5C netrin receptor gene that segregated with disease in an autosomal dominant pattern in two families enriched for late-onset ...Alzheimer's disease and that was associated with disease across four large case-control cohorts (odds ratio = 2.15, Pmeta = 0.0095). T835M alters a conserved residue in the hinge region of UNC5C, and in vitro studies demonstrate that this mutation leads to increased cell death in human HEK293T cells and in rodent neurons. Furthermore, neurons expressing T835M UNC5C are more susceptible to cell death from multiple neurotoxic stimuli, including β-amyloid (Aβ), glutamate and staurosporine. On the basis of these data and the enriched hippocampal expression of UNC5C in the adult nervous system, we propose that one possible mechanism in which T835M UNC5C contributes to the risk of Alzheimer's disease is by increasing susceptibility to neuronal cell death, particularly in vulnerable regions of the Alzheimer's disease brain.
To identify genetic mechanisms involved in the interplay of risky sexual behaviors (RSBs) and alcohol dependence (AD), we conducted genome-wide gene-by-AD (GW-GxAD) analyses of RSB in 3924 ...alcohol-exposed and sexually experienced subjects. RSBs were defined as a score based on lifetime experiences of unprotected sex and multiple sexual partners. Diagnosis of lifetime AD was defined by DSM-IV criteria. To follow-up the genetic findings, functional magnetic resonance imaging analyses were conducted in an independent sample. A trans-population genome-wide significant signal was identified in LHPP (rs34997829; z=-5.573, p=2.51 × 10
) in the GxAD analysis that also showed associations in the AD-stratified association analysis (AD z=-2.032 and non-AD z=4.903). The clinical relevance of the result was confirmed by the significant interaction between LHPP rs34997829 and AD with respect to self-reported sexually transmitted disease (STD; z=-2.809, p=4.97 × 10
). The neuroimaging follow-up analysis of LHPP rs34997829 showed reduced power of the left superior frontal gyrus (t=-3.386, p=9.56 × 10
) and increased power at the right amygdala (t=3.287, p=1.33 × 10
) in the resting amplitude of low frequency fluctuations analysis; and reduced activation of the anterior cingulate region (t=-2.961, p=3.69 × 10
) in the monetary incentive delay task. In conclusion, LHPP locus is associated to AD-RSB interaction; and with brain circuitries previously implicated in the inhibition of risky behavior and impulsiveness, emotional regulation, and impulse control/error monitoring. Thus, LHPP is a strong candidate to influence RSB and STD risk in the context of AD.
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