Biology subjects

Demirkan, A.

Publications and source records attributed to Demirkan, A..

3 recordsLinked to original sources

bioRxiv2019

Genome-wide association study of plasma lipids

There is continuous interest in the genetic determinants of plasma triglycerides (TGs) and phospholipids and their role in the etiology of cardiovascular disease (CVD). Here, we report the results of a Dutch genome wide association study (GWAS) of an in-house developed lipidomics platform, focusing on 90 plasma lipids. Lipids were assessed by liquid chromatography mass spectrometry in participants from the Leiden Longevity Study, the Netherlands Twin Register and the Erasmus Rucphen Family (ERF) study and meta-analysed, resulting in a sample size of 5537 participants. In addition, we performed genetic correlation analyses between the 90 plasma lipids and markers of metabolic health, as well as vascular pathology and CVD combining our GWAS results with publicly available GWAS outputs. We replicated previously known associations between 34 lipids and 10 lipid quantitative trait loci (lipQTL) (GCKR, APOA1, FADS1, SGPP1,TMEM229B, LIPC, PDXDC1, CETP, CERS4 and SPTLC3) with metabolome-wide (P < 1.61 x 10-9) significance. Moreover, we report 6 novel phospholipid-related and 5 triglyceride (TG)-related loci: SGGP1 (SM21:0), SPTLC3 (SM21:0 and SM25:1), FADS1 (LPCO16:1, PC38:2, PEO36:5, PEO38:5, TG56:5, TG56:6, and TG56:7), TMEM229 (LPCO16:1), GCKR (TG50:2), and APOA1 (TG54:4). In addition, we report suggestively significant (P < 5 x 10-8) associations mapping to eleven novel lipid quantitative trait loci (lipQTLs), three of which are supported by mining previous GWAS data: MAU (PC34:4), LDLR (SM16:0), and MLXIPL (TG48:1 and TG50:1)). Genetic correlation analysis indicates that one specific specific sphingomyelin, SM22:0, shares common genetic background with CVD. Levels of SM22:0 also positively associate with carotid artery intima-media thickness in the ERF study, and this observation is independent of LDL-C level. Our findings yield higher resolution of plasma lipid species and new insights in the biology of circulating phosholipids and their relation to CVD risk.

epidemiology↗

bioRxiv2019

Effect of inbreeding on type 2 diabetes-related metabolites in a Dutch genetic isolate

Autozygosity, meaning inheritance of an ancestral allele in the homozygous state is known to lead bi-allelic mutations that manifest their effects through the autosomal recessive inheritance pattern. Autosomal recessive mutations are known to be the underlying cause of several Mendelian metabolic diseases, especially among the offspring of related individuals. In line with this, inbreeding coefficient of an individual as a measure of cryptic autozygosity among the general population is known to lead adverse metabolic outcomes including type 2 diabetes (T2DM), a multifactorial metabolic disease for which the recessive genetic causes remain unknown. In order to unravel such effects for multiple metabolic facades of the disease, we investigated the relationship between the excess of homozygosity and the metabolic signature of T2DM. We included a set of heritable 143 circulating markers associated with fasting glucose in a Dutch genetic isolate Erasmus Rucphen Family (ERF) of up to 2,580 individuals. We calculated individual whole genome-based, exome-based and pedigree-based inbreeding coefficients and tested their influence on the T2DM-related metabolites as well as T2DM risk factors. We also performed model supervised genome-wide association analysis (GWAS) for the metabolites which significantly correlate with inbreeding values. Inbreeding value of the population significantly and positively correlated with associated with risk factors of T2DM: body-mass index (BMI), glucose, insulin resistance, fasting insulin and waist-hip ratio. We found that inbreeding influenced 32.9% of the T2DM-related metabolites, clustering among chemical groups of lipoproteins, amino-acids and phosphatidylcholines, whereas 80 % of these significant associations were independent of the BMI. The most remarkable effect of inbreeding is observed for S-HDL-ApoA1, for which we show evidence of the novel DISP1 genetic region discovered by model supervised GWAS, in the ERF population. In conclusion, we show that inbreeding effects human metabolism and genetic models other than the globally used additive model is worth considering for study of metabolic phenotypes.

genetics↗

bioRxiv2019

Recessive genetic effects on type 2 diabetes-related metabolites in a consanguineous population

Autozygosity, meaning inheritance of an ancestral allele in the homozygous state is known to lead bi-allelic mutations that manifest their effects through the autosomal recessive inheritance pattern. Autosomal recessive mutations are known to be the underlying cause of several Mendelian metabolic diseases, especially among the offspring of related individuals. In line with this, inbreeding coefficient of an individual as a measure of cryptic autozygosity among the general population is known to lead adverse metabolic outcomes including Type 2 diabetes (T2DM); a multifactorial metabolic disease for which the recessive genetic causes remain unknown. In order to unravel such effects for multiple metabolic facades of the disease, we investigated the relationship between the excess of homozygosity and the metabolic signature of T2DM. We included a set of 53 metabolic phenotypes, including 47 metabolites, T2DM and five T2DM risk factors, measured in a Dutch genetic isolate of 2,580 people. For 20 of these markers, we identified 29 regions of homozygous (ROHs) associated with the nominal significance of P-value < 1.0 x 10-3. By performing association according to the recessive genetic model within these selected regions, we identified and replicated two intronic variants: rs6759814 located in KCNH7 associated with valine and rs1573707 located in PTPRT associated with IDL-free cholesterol and IDL-phospholipids. Additionally, we identified a rare intronic SNV in TBR1 for which the homozygous individuals were enriched for obesity. Interestingly, all three genes are mainly neuronally expressed and pointed out the involvement of glutamergic synaptic transmission pathways in the regulation of metabolic pathways. Taken together our study underline the additional benefits of model supervised analysis, but also seconds the involvement of the central nervous system in T2DM and obesity pathogenesis.

genetics↗