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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 × 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.

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