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Identifying novel chronotype loci
Our sleep timing preference, or chronotype, is a manifestation of our internal biological clock. Variation in chronotype (eveningness, morningness, etc) has been linked to sleep disorders, cognitive and physical performance, and chronic disease.
In this study we performed a genome-wide association study of self-reported chronotype in 100,420 individuals, and our results identify 12 new genetic loci relevant to the circadian clock. The discovered loci also affect central nervous system, ocular systems, and fear-response processes. Using a technique called Mendelian randomization, we additionally show that evening chronotype relates to higher educational attainment. These data motivate our study of the causal links between circadian genetics and life-history outcomes, like educational attainment.
Type 2 diabetes risk and a mutant melatonin receptor
The risk of developing type 2 diabetes (T2D) is increased by poor sleep hygiene, circadian misalignment, and melatonin dysregulation. A common genetic variant in a melatonin receptor (MTNR1B) is associated with increased fasting blood glucose and risk of T2D.
We sought to test if the identified MTNR1B risk allele altered sleep, and used actigraphy, polysomnography, and other intensive measures of sleep to do so. Our results provided the insight that the MTNR1B risk allele influences the timing of melatonin secretion, theoretically by extending the duration of melatonin secretion later into the morning. Further research seeks to find out if early waking magnifies the diabetes risk conferred by the risk allele.
Linking dopamine receptor variants to sleep duration
Sleep duration is implicated in the etiologies of chronic diseases and premature mortality. However, the genetic basis for sleep duration is poorly defined.
We sought to identify novel genetic components influencing sleep duration in a multi-ethnic sample. We conducted meta-analyses on 25,000 individuals of African, Asian, European, and Hispanic American ancestry. After genotyping and analyzing ∼50,000 SNPs from heart, lung, blood and sleep genes, we found the dopamine receptor DRD2 to be significantly associated with sleep duration. After controlling for this effect, we identified a second DRD2 signal with an opposite effect on sleep duration. Our work motivates future research on wakefulness agents (caffeine, modafinil, etc) that influence the dopamine pathway.
Validating a pre-eclampsia risk allele in multiple populations
Pre-eclampsia is a pregnancy disorder characterized by high levels of protein in the urine, hypertension, liver and kidney dysfunction, and significant maternal and fetal morbidity.
To identify maternal genes associated with pre-eclampsia risk, we assembled 498 cases and 1864 controls of European ancestry and genotyped the samples on a cardiovascular gene array. Nine lead signals were identified, and we then performed genetic analyses in samples of black, Hispanic, and East Asian ancestry, which revealed a significant association of a variant in the PLEKHG1 gene. PLEKHG1 variants have previously been implicated in studies of blood pressure, body weight, and neurological disorders. This study identifies a novel maternal risk locus, and we seek to further define maternal pre-eclampsia heritability with larger studies.