-
1.
Circulating Metabolome and White Matter Hyperintensities in Women and Men.
Sliz, E, Shin, J, Ahmad, S, Williams, DM, Frenzel, S, Gauß, F, Harris, SE, Henning, AK, Hernandez, MV, Hu, YH, et al
Circulation. 2022;(14):1040-1052
-
-
Free full text
-
Abstract
BACKGROUND White matter hyperintensities (WMH), identified on T2-weighted magnetic resonance images of the human brain as areas of enhanced brightness, are a major risk factor of stroke, dementia, and death. There are no large-scale studies testing associations between WMH and circulating metabolites. METHODS We studied up to 9290 individuals (50.7% female, average age 61 years) from 15 populations of 8 community-based cohorts. WMH volume was quantified from T2-weighted or fluid-attenuated inversion recovery images or as hypointensities on T1-weighted images. Circulating metabolomic measures were assessed with mass spectrometry and nuclear magnetic resonance spectroscopy. Associations between WMH and metabolomic measures were tested by fitting linear regression models in the pooled sample and in sex-stratified and statin treatment-stratified subsamples. Our basic models were adjusted for age, sex, age×sex, and technical covariates, and our fully adjusted models were also adjusted for statin treatment, hypertension, type 2 diabetes, smoking, body mass index, and estimated glomerular filtration rate. Population-specific results were meta-analyzed using the fixed-effect inverse variance-weighted method. Associations with false discovery rate (FDR)-adjusted P values (PFDR)<0.05 were considered significant. RESULTS In the meta-analysis of results from the basic models, we identified 30 metabolomic measures associated with WMH (PFDR<0.05), 7 of which remained significant in the fully adjusted models. The most significant association was with higher level of hydroxyphenylpyruvate in men (PFDR.full.adj=1.40×10-7) and in both the pooled sample (PFDR.full.adj=1.66×10-4) and statin-untreated (PFDR.full.adj=1.65×10-6) subsample. In men, hydroxyphenylpyruvate explained 3% to 14% of variance in WMH. In men and the pooled sample, WMH were also associated with lower levels of lysophosphatidylcholines and hydroxysphingomyelins and a larger diameter of low-density lipoprotein particles, likely arising from higher triglyceride to total lipids and lower cholesteryl ester to total lipids ratios within these particles. In women, the only significant association was with higher level of glucuronate (PFDR=0.047). CONCLUSIONS Circulating metabolomic measures, including multiple lipid measures (eg, lysophosphatidylcholines, hydroxysphingomyelins, low-density lipoprotein size and composition) and nonlipid metabolites (eg, hydroxyphenylpyruvate, glucuronate), associate with WMH in a general population of middle-aged and older adults. Some metabolomic measures show marked sex specificities and explain a sizable proportion of WMH variance.
-
2.
Global and Regional Development of the Human Cerebral Cortex: Molecular Architecture and Occupational Aptitudes.
Shin, J, Ma, S, Hofer, E, Patel, Y, Vosberg, DE, Tilley, S, Roshchupkin, GV, Sousa, AMM, Jian, X, Gottesman, R, et al
Cerebral cortex (New York, N.Y. : 1991). 2020;(7):4121-4139
-
-
Free full text
-
Abstract
We have carried out meta-analyses of genome-wide association studies (GWAS) (n = 23 784) of the first two principal components (PCs) that group together cortical regions with shared variance in their surface area. PC1 (global) captured variations of most regions, whereas PC2 (visual) was specific to the primary and secondary visual cortices. We identified a total of 18 (PC1) and 17 (PC2) independent loci, which were replicated in another 25 746 individuals. The loci of the global PC1 included those associated previously with intracranial volume and/or general cognitive function, such as MAPT and IGF2BP1. The loci of the visual PC2 included DAAM1, a key player in the planar-cell-polarity pathway. We then tested associations with occupational aptitudes and, as predicted, found that the global PC1 was associated with General Learning Ability, and the visual PC2 was associated with the Form Perception aptitude. These results suggest that interindividual variations in global and regional development of the human cerebral cortex (and its molecular architecture) cascade-albeit in a very limited manner-to behaviors as complex as the choice of one's occupation.
-
3.
Outcomes of Vocal Fold Motion Impairment and Dysphagia after Pediatric Cardiothoracic Surgery: A Systematic Review.
Orzell, S, Joseph, R, Ongkasuwan, J, Bedwell, J, Shin, J, Raol, N
Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery. 2019;(5):754-763
Abstract
OBJECTIVE The objective of this study was to systematically review the literature regarding vocal fold motion impairment (VFMI), respiratory outcomes, and swallowing outcomes in children following congenital heart surgery (CHS). DATA SOURCES PubMed, Embase, Medline, and CINAHL databases. REVIEW METHODS Data sources were searched from inception to November 30, 2018. Studies that described recovery of VFMI and swallowing function following CHS were included, and a qualitative analysis was performed. RESULTS A total of 1371 studies were identified, of which 8 met inclusion criteria for VFMI and 5 met inclusion criteria for swallowing outcomes. Studies including patients who underwent isolate patent ductus arteriosus ligation were excluded. VFMI was present in 8% to 59% of subjects, and rates of recovery ranged from 9% to 96% at 6 months to 6 years of follow-up. Inability to maintain an oral diet occurred in 14% to 100% of subjects with VFMI and 11% to 61% without VFMI following surgery. Tolerance of an oral diet without tube feeding was present in 66% to 75% of subjects with VFMI and 88% to 100% without VFMI at 24 days to 3.2 years of follow-up. Limited data suggest that time to extubation is longer in VFMI subjects, but overall hospital length of stay and mortality may not be affected by VFMI status. CONCLUSIONS Data evaluating dysphagia and VFMI after CHS are limited. Most studies suggest significant improvement in swallowing function, while rate of recovery of VFMI is variable. Future prospective studies with standardized screening and follow-up are needed to better elucidate outcomes to help develop algorithms for identification and management of VFMI after CHS.
-
4.
Genome-wide meta-analysis of macronutrient intake of 91,114 European ancestry participants from the cohorts for heart and aging research in genomic epidemiology consortium.
Merino, J, Dashti, HS, Li, SX, Sarnowski, C, Justice, AE, Graff, M, Papoutsakis, C, Smith, CE, Dedoussis, GV, Lemaitre, RN, et al
Molecular psychiatry. 2019;(12):1920-1932
-
-
Free full text
-
Abstract
Macronutrient intake, the proportion of calories consumed from carbohydrate, fat, and protein, is an important risk factor for metabolic diseases with significant familial aggregation. Previous studies have identified two genetic loci for macronutrient intake, but incomplete coverage of genetic variation and modest sample sizes have hindered the discovery of additional loci. Here, we expanded the genetic landscape of macronutrient intake, identifying 12 suggestively significant loci (P < 1 × 10-6) associated with intake of any macronutrient in 91,114 European ancestry participants. Four loci replicated and reached genome-wide significance in a combined meta-analysis including 123,659 European descent participants, unraveling two novel loci; a common variant in RARB locus for carbohydrate intake and a rare variant in DRAM1 locus for protein intake, and corroborating earlier FGF21 and FTO findings. In additional analysis of 144,770 participants from the UK Biobank, all identified associations from the two-stage analysis were confirmed except for DRAM1. Identified loci might have implications in brain and adipose tissue biology and have clinical impact in obesity-related phenotypes. Our findings provide new insight into biological functions related to macronutrient intake.
-
5.
Genome-wide association meta-analysis of age at first cannabis use.
Minică, CC, Verweij, KJH, van der Most, PJ, Mbarek, H, Bernard, M, van Eijk, KR, Lind, PA, Liu, MZ, Maciejewski, DF, Palviainen, T, et al
Addiction (Abingdon, England). 2018;(11):2073-2086
-
-
Free full text
-
Abstract
BACKGROUND AND AIMS Cannabis is one of the most commonly used substances among adolescents and young adults. Earlier age at cannabis initiation is linked to adverse life outcomes, including multi-substance use and dependence. This study estimated the heritability of age at first cannabis use and identified associations with genetic variants. METHODS A twin-based heritability analysis using 8055 twins from three cohorts was performed. We then carried out a genome-wide association meta-analysis of age at first cannabis use in a discovery sample of 24 953 individuals from nine European, North American and Australian cohorts, and a replication sample of 3735 individuals. RESULTS The twin-based heritability for age at first cannabis use was 38% [95% confidence interval (CI) = 19-60%]. Shared and unique environmental factors explained 39% (95% CI = 20-56%) and 22% (95% CI = 16-29%). The genome-wide association meta-analysis identified five single nucleotide polymorphisms (SNPs) on chromosome 16 within the calcium-transporting ATPase gene (ATP2C2) at P < 5E-08. All five SNPs are in high linkage disequilibrium (LD) (r2 > 0.8), with the strongest association at the intronic variant rs1574587 (P = 4.09E-09). Gene-based tests of association identified the ATP2C2 gene on 16q24.1 (P = 1.33e-06). Although the five SNPs and ATP2C2 did not replicate, ATP2C2 has been associated with cocaine dependence in a previous study. ATP2B2, which is a member of the same calcium signalling pathway, has been associated previously with opioid dependence. SNP-based heritability for age at first cannabis use was non-significant. CONCLUSION Age at cannabis initiation appears to be moderately heritable in western countries, and individual differences in onset can be explained by separate but correlated genetic liabilities. The significant association between age of initiation and ATP2C2 is consistent with the role of calcium signalling mechanisms in substance use disorders.
-
6.
Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32 330 subjects from the International Cannabis Consortium.
Stringer, S, Minică, CC, Verweij, KJ, Mbarek, H, Bernard, M, Derringer, J, van Eijk, KR, Isen, JD, Loukola, A, Maciejewski, DF, et al
Translational psychiatry. 2016;(3):e769
Abstract
Cannabis is the most widely produced and consumed illicit psychoactive substance worldwide. Occasional cannabis use can progress to frequent use, abuse and dependence with all known adverse physical, psychological and social consequences. Individual differences in cannabis initiation are heritable (40-48%). The International Cannabis Consortium was established with the aim to identify genetic risk variants of cannabis use. We conducted a meta-analysis of genome-wide association data of 13 cohorts (N=32 330) and four replication samples (N=5627). In addition, we performed a gene-based test of association, estimated single-nucleotide polymorphism (SNP)-based heritability and explored the genetic correlation between lifetime cannabis use and cigarette use using LD score regression. No individual SNPs reached genome-wide significance. Nonetheless, gene-based tests identified four genes significantly associated with lifetime cannabis use: NCAM1, CADM2, SCOC and KCNT2. Previous studies reported associations of NCAM1 with cigarette smoking and other substance use, and those of CADM2 with body mass index, processing speed and autism disorders, which are phenotypes previously reported to be associated with cannabis use. Furthermore, we showed that, combined across the genome, all common SNPs explained 13-20% (P<0.001) of the liability of lifetime cannabis use. Finally, there was a strong genetic correlation (rg=0.83; P=1.85 × 10(-8)) between lifetime cannabis use and lifetime cigarette smoking implying that the SNP effect sizes of the two traits are highly correlated. This is the largest meta-analysis of cannabis GWA studies to date, revealing important new insights into the genetic pathways of lifetime cannabis use. Future functional studies should explore the impact of the identified genes on the biological mechanisms of cannabis use.