Integrative Identification of Genetic Loci Jointly Influencing Diabetes-Related Traits and Sleep Traits of Insomnia, Sleep Duration, and Chronotypes

Abstract

Accumulating evidence suggests a relationship between type 2 diabetes mellitus and sleep problems. A comprehensive study is needed to decipher whether shared polygenic risk variants exist between diabetic traits and sleep traits. Methods: We integrated summary statistics from different genome-wide association studies and investigated overlap in single-nucleotide polymorphisms (SNPs) associated with diabetes-related traits (type 2 diabetes, fasting glucose, fasting insulin, and glycated hemoglobin) and sleep traits (insomnia symptoms, sleep duration, and chronotype) using a conditional/conjunctional false discovery rate approach. Pleiotropic genes were further evaluated for differential expression analysis, and we assessed their expression pattern effects on type 2 diabetes by Mendelian randomization (MR) analysis. Results: We observed extensive polygenic pleiotropy between diabetic traits and sleep traits. Fifty-eight independent genetic loci jointly influenced the risk of type 2 diabetes and the sleep traits of insomnia, sleep duration, and chronotype. The strongest shared locus between type 2 diabetes and sleep straits was FTO (lead SNP rs8047587). Type 2 diabetes (z score, 16.19; P = 6.29 × 10−59) and two sleep traits, sleep duration (z score, −6.66; P = 2.66 × 10−11) and chronotype (z score, 7.42; P = 1.19 × 10−13), were shared. Two of the pleiotropic genes, ENSA and PMPCA, were validated to be differentially expressed in type 2 diabetes, and PMPCA showed a slight protective effect on type 2 diabetes in MR analysis. Conclusions: Our study provided evidence for the polygenic overlap between diabetic traits and sleep traits, of which the expression of PMPCA may play a crucial role and provide support of the hazardous effect of being an “evening” person on diabetes risk.

Sex-specific genetic loci linked to early and late onset type 2 diabetes

“…The importance of parental history on T2D development has been well established in both family (6)(7)(8) and association studies (9). The heritability of T2D is variable, reported to be around 25% in family studies (9)(10)(11) and 20% in association studies (6,7,12). In a casecontrol study conducted in Mexico, the R 2 of T2D attributed to parental history of diabetes was 12.1%.…”

Mendelian randomization study of sleep traits and risk of colorectal cancer

“…Although data linking chronotype and insomnia with CRC risk are limited, Mendelian randomization (MR), a common approach to address inherent biases in observational studies, has also been widely adopted to study the association of sleep-related traits with several outcomes, including breast [9,10] and prostate cancer [10], as well as known risk factors of CRC, such as adiposity [11] and type 2 diabetes mellitus (T2DM) [12]. MR studies have reported that morning preference was associated with increased T2DM risk [13], alcohol consumption [14], educational attainment [15] , and reduced risks of breast [9,10] and prostate cancer [10]; insomnia was associated with an increased T2DM risk, higher body mass index (BMI) and a decrease in educational attainment [7]; increased sleep duration was associated with an increased risk of breast cancer [9] and a higher BMI in children [8] and, lastly, short sleep duration was associated with an increased CRC risk using data from UK Biobank (UKB) based on 5,486 CRC cases [16]. To our knowledge, there is no other MR study that has investigated the potential association between sleep-related traits and CRC risk.…”