Prof. Rui Lin
Guangxi Medical University, China
Title: Low-coverage whole genome sequencing identify four loci for serum melatonin and its causal relationship with hypertension
Abstract:
Background Melatonin is a natural hormone mainly secreted by the pineal gland and has been widely used as a sleep aid. It also has multiple extraordinary functions since its receptors are widely expressed at central and peripheral sites. Recently, clinical trials have illustrated the beneficial effects of melatonin supplement in lowering hypertension, type 2 diabetes (T2D) and their related traits such as body mass index (BMI) and lipid profile, while mixed results were illustrated. The controversial results might due to different dosage, preparation (immediate-release vs prolonged-release), duration use (short-term vs long-term), time of use (daytime vs bedtime) of melatonin supplement, and the genetic background of the participants. However, little is known about the genetic architecture of melatonin and its genetic causal association with chronic disease. Previously, a genome-wide association study (GWAS) of melatonin secretion has indicated a suggestive association signal but not genome-wide significant by using genotyping array and the indicator of morning urine 6-hydroxymelatonin sulfate-to-creatinine ratio with a relative small sample size. In the present study, we conducted a GWAS for serum melatonin using low-coverage whole genome sequencing (lcWGS) with a larger sample size. We aimed to detect the loci conferring susceptibility to serum melatonin and, from genetic aspect, to explore the association of serum melatonin with risk of T2D, hypertension and their related phenotypes such as obesity and dyslipidemia. We also examined their causal relationships by performing one-sample Mendelian randomization (MR) analysis.
Methods We performed low-coverage whole-genome sequencing (lcWGS) on 3,791 Han Chinese adults and a Genome-wide association study (GWAS) for serum melatonin included 3,605 individuals. Melatonin intervention animal experiment was conducted to confirm the association of the GWAS-identified genes with melatonin and subsequence T2D and hypertension. Genetic risk score (GRS) based-association analyses and one-sample Mendelian Randomization (MR) analysis was conducted for investigating the genetic causal association between serum melatonin and T2D, hypertension and their related phenotypes.
Findings A total of 17,275,409 autosomal SNPs were identified with a mean depth of 1.2× and an imputation quality score of 0.999. Four low-frequency variants were identified to be genome-wide significantly associated with serum melatonin: two in the intron of the LINC01807 (rs181919487, p=1•00×10-9, MAF=0•9%) and PTPRD gene (rs150169882, p=4•08×10-8, MAF=0•6%), two located the intergenic of EDIL3 and NBPF22P (rs1162213, p= 3•22×10-8, MAF=0•9%) and of LMO1 and STK33 (rs183044124, p=3•74×10-8, MAF=2•2%). Melatonin intervention significantly upregulated the expressions of PTPRD, EDIL3, and LMO1 in the mice aortic arch, while down regulated the expressions of PTPRD, EDIL3, LMO1 and STK33 in the colon (all p<0•05). High low-serum melatonin-GRS was associated with increased hypertension risk (OR=2.18, p=0.019), high levels of systolic blood pressure (SBP, β=4.21, p=0.012) and diastolic blood pressure (DBP, β=3.19, p=0.006). Genetically predicted serum melatonin level was negatively associated with hypertension risk (OR =0.47, p= 0.019), levels of SBP (β =-4.11, p=0.012) and DBP (β=-3.11, p=0.006). No causal relationship was observed between serum melatonin and T2D, obesity or dyslipidemia.
Interpretation Using lcWGS, four loci were identified being genome-wide significantly associated with serum melatonin. A protective causal relationship was between serum melatonin and hypertension. Further research is warranted to validate our findings.
Funding The National Natural Science Foundation of China (no. 82273618, 82060593), Natural Science Foundation of Guangxi Province (no. 2018GXNSFDA050019), Major Project of Guangxi Innovation Driven (no. AA18118016) and the National Key Research and Development Program of China (no 2017YFC0908000).
Biography:
Dr Rui Lin (MD. Ph.D) now is a Professor of epidemiology of School of Public Health and Center for Genomic and Personalized Medicine, Guangxi Medical University, China. She studied in Karolinska Institute, Sweden on cancer epidemiology as a visiting scholar in 2006-2007, and got her Ph.D in genetic epidemiology at University of Tasmania, Australia in 2014. She awarded Australian Endeavour International Postgraduate Research Scholarship (EIPRS) and the Hundred Talents Program of Higher Education Institution of Guangxi Province, China. She is the member of the American Nutrition Society and the first council of the Chinese Medicine Health Products Professional Committee of the World Federation of Chinese Medicine Societies, and the editor of Applied Preventive Medicine, and the reviewer of Critical Reviews in Food Science and Nutrition, iMeta, Gut Microbes, etc.
Dr. Rui Lin is the PI of three National Natural Science Foundation of China projects and four of provincial and ministerial level projects. Recently she has published 11 SCI papers as the first author/corresponding author in Diabetologia (2022), European J of Nutrition (2022), Chemosphere (2021), JNNP (2014), etc. Her researches currently focus on nutrition, genetic epidemiology and microbiome of type 2 diabetes.