scholarly journals Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use

2019 ◽  
Vol 85 (11) ◽  
pp. 946-955 ◽  
Author(s):  
David M. Brazel ◽  
Yu Jiang ◽  
Jordan M. Hughey ◽  
Valérie Turcot ◽  
Xiaowei Zhan ◽  
...  
2021 ◽  
Author(s):  
Frida Lona-Durazo ◽  
Rohit Thakur ◽  
Erola Pairo-Castineira ◽  
Karen Funderburk ◽  
Tongwu Zhang ◽  
...  

The main factors that determine eye colour are the amount of melanin concentrated in iris melanocytes, as well as the shape and distribution of melanosomes. Eye colour is highly variable in populations with European ancestry, in which eye colour categories cover a continuum of low to high quantities of melanin accumulated in the iris. A few polymorphisms in the HERC2/OCA2 locus in chromosome 15 have the largest effect on eye colour in these populations, although there is evidence of other variants in the locus and across the genome also influencing eye colour. To improve our understanding of the genetic loci determining eye colour, we performed a meta-analysis of genome-wide association studies in a Canadian cohort of European ancestry (N= 5,641) and investigated putative causal variants. Our fine-mapping results indicate that there are several candidate causal signals in the HERC2/OCA2 region, whereas other significant loci in the genome likely harbour a single causal signal (TYR, TYRP1, IRF4, SLC24A4). Furthermore, a short subset of the associated eye colour regions was colocalized with the gene expression or methylation profiles of cultured melanocytes (HERC2, OCA2), and transcriptome-wide association studies highlighted the expression of two genes associated with eye colour: SLC24A4 and OCA2. Finally, genetic correlations of eye and hair colour from the same cohort suggest high pleiotropy at the genome level, but locus-level evidence hints at several differences in the genetic architecture of both traits. Overall, we provide a better picture of how polymorphisms modulate eye colour variation, particularly in the HERC2/OCA2 locus, which may be a consequence of specific molecular processes in the iris melanocytes.


2018 ◽  
Author(s):  
Joao Ricardo Nickenig Vissoci

BackgroundHarmful alcohol use leads to a large burden of disease and disability which disportionately impacts LMICs. The World Health Organization and the Lancet have issued calls for this burden to be addressed, but issues remain, primarily due to gaps in information. While a variety of interventions have been shown to be effective at reducing alcohol use in HICs, their efficacy in LMICs have yet to be assessed. This systematic review describes the current published literature on alcohol interventions in LMICs and conducts a meta analysis of clinical trials evaluating interventions to reduce alcohol use and harms in LMICs.MethodsIn accordance with PRISMA guidelines we searched the electronic databases Pubmed, EMBASE, Scopus,Web of Science, Cochrane, and Psych Info. Articles were eligible if they evaluated an intervention targeting alcohol-related harm in LMICs. After a reference and citation analysis, we conducted a quality assessment per PRISMA protocol. A meta-analysis was performed on the 39 randomized controlled trials that evaluated an alcohol-related outcome.ResultsOf the 3,801 articles from the literature search, 87 articles from 25 LMICs fit the eligibility and inclusion criteria. Of these studies, 39 randomized controlled trials were included in the meta-analysis. Nine of these studies focused specifically on medication, while the others focused on brief motivational intervention, brain stimulation, AUDIT-based brief interventions, WHO ASSIST-based interventions, group based education, basic screening and interventions, brief psychological or counseling, dyadic relapse prevention, group counseling, CBT, motivational + PTSD based interview, and health promotion/awareness. Conclusion Issues in determining feasible options specific to LMICs arise from unstandardized interventions, unequal geographic distribution of intervention implementation, and uncertain effectiveness over time. Current research shows that brain stimulation, psychotherapy, and brief motivational interviews have the potential to be effective in LMIC settings, but further feasibility testing and efforts to standardize results are necessary to accurately assess their effectiveness.


2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Do Hyeon Cha ◽  
Heon Yung Gee ◽  
Raul Cachau ◽  
Jong Mun Choi ◽  
Daeui Park ◽  
...  

Abstract Differentiating between inherited renal hypouricemia and transient hypouricemic status is challenging. Here, we aimed to describe the genetic background of hypouricemia patients using whole-exome sequencing (WES) and assess the feasibility for genetic diagnosis using two founder variants in primary screening. We selected all cases (N = 31) with extreme hypouricemia (<1.3 mg/dl) from a Korean urban cohort of 179,381 subjects without underlying conditions. WES and corresponding downstream analyses were performed for the discovery of rare causal variants for hypouricemia. Two known recessive variants within SLC22A12 (p.Trp258*, pArg90His) were identified in 24 out of 31 subjects (77.4%). In an independent cohort, we identified 50 individuals with hypouricemia and genotyped the p.Trp258* and p.Arg90His variants; 47 of the 50 (94%) hypouricemia cases were explained by only two mutations. Four novel coding variants in SLC22A12, p.Asn136Lys, p.Thr225Lys, p.Arg284Gln, and p.Glu429Lys, were additionally identified. In silico studies predict these as pathogenic variants. This is the first study to show the value of genetic diagnostic screening for hypouricemia in the clinical setting. Screening of just two ethnic-specific variants (p.Trp258* and p.Arg90His) identified 87.7% (71/81) of Korean patients with monogenic hypouricemia. Early genetic identification of constitutive hypouricemia may prevent acute kidney injury by avoidance of dehydration and excessive exercise.


BMJ ◽  
2015 ◽  
Vol 350 (jan12 13) ◽  
pp. g7772-g7772 ◽  
Author(s):  
M. Virtanen ◽  
M. Jokela ◽  
S. T. Nyberg ◽  
I. E. H. Madsen ◽  
T. Lallukka ◽  
...  

2021 ◽  
pp. 1-10
Author(s):  
Sophie E. Legge ◽  
Marcos L. Santoro ◽  
Sathish Periyasamy ◽  
Adeniran Okewole ◽  
Arsalan Arsalan ◽  
...  

Abstract Schizophrenia is a severe psychiatric disorder with high heritability. Consortia efforts and technological advancements have led to a substantial increase in knowledge of the genetic architecture of schizophrenia over the past decade. In this article, we provide an overview of the current understanding of the genetics of schizophrenia, outline remaining challenges, and summarise future directions of research. World-wide collaborations have resulted in genome-wide association studies (GWAS) in over 56 000 schizophrenia cases and 78 000 controls, which identified 176 distinct genetic loci. The latest GWAS from the Psychiatric Genetics Consortium, available as a pre-print, indicates that 270 distinct common genetic loci have now been associated with schizophrenia. Polygenic risk scores can currently explain around 7.7% of the variance in schizophrenia case-control status. Rare variant studies have implicated eight rare copy-number variants, and an increased burden of loss-of-function variants in SETD1A, as increasing the risk of schizophrenia. The latest exome sequencing study, available as a pre-print, implicates a burden of rare coding variants in a further nine genes. Gene-set analyses have demonstrated significant enrichment of both common and rare genetic variants associated with schizophrenia in synaptic pathways. To address current challenges, future genetic studies of schizophrenia need increased sample sizes from more diverse populations. Continued expansion of international collaboration will likely identify new genetic regions, improve fine-mapping to identify causal variants, and increase our understanding of the biology and mechanisms of schizophrenia.


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