I am scientist specialized in metabolism and genetics.
Genetic factors can lead to a disruption of sleep, with consequences on metabolism and behavior.
In 10 seconds? On top of external causes, genetic background emerges as an important factor for disrupting the circadian sleep/wake cycle, causing metabolic and psychological disorders, specially in children, adolescents and young adults.
Don’t believe it? The circadian clock, a supraphysiological system that organizes the different biological functions in 24 h, such as sleep/wake, temperature, heart rate, glucose level and oxidative stress, is conducted and regulated by some genes, named clock genes, and several single nucleotide polymorphisms found in these genes have been associated to a number of health disorders.
What genes are involved? The biological clock is organized by a transcriptional/translational feedback loop of clock genes named Clock, Bmal1, Per1–3, and Cry1-2, as well as modulators which give it a fine tuning. Even variants in non-coding RNA’s, as the deletion responsible of the Prader-Willi syndrome, have an impact on these genes and on the circadian rhythm.
What may be the consequences? Disregulations of the circadian sleep/wake rhythm lead to several health problems, such as the Night Eating Syndrome, obesity, type 2 diabetes, as well as elevated risk of developing mood disorders such as bipolar disorder, depression or Attention-deficit hyperactivity disorder, one of the most common psychiatric disorders in children with prevalence rates of up to 10% among those aged 6 to 17 years old.
And what can be done? Pinpointing these gene variants may help identify individuals who are more susceptible to overeating and gaining weight when exposed to short sleep durations, and longer habitual sleep duration could ameliorate their genetic predisposition.
Abstract: Attention-deficit hyperactivity disorder (ADHD) is notorious for its debilitating consequences and early age of onset. The need for early diagnosis and intervention has frequently been underscored. Previous studies have attempted to clarify the bidirectional relationship between ADHD and sleep problems, proposing a potential role for sleep problems as early predictors of ADHD. Sleep deprivation, sleep-disordered breathing, and circadian rhythm disturbances have been extensively studied, yielding evidence with regard to their induction of ADHD-like symptoms. Genetic-phenotypic differences across individuals regarding the aforementioned sleep problems have been elucidated along with the possible use of these characteristics for early prediction of ADHD. The long-term consequences of sleep problems in individuals with ADHD include obesity, poor academic performance, and disrupted parent-child interactions. Early intervention has been proposed as an approach to preventing these debilitating outcomes of ADHD, with novel treatment approaches ranging from melatonin and light therapy to myofunctional therapy and adjustments of the time point at which school starts.
Pub.: 01 Feb '17, Pinned: 27 Apr '17
Abstract: Disrupted circadian rhythms and reduced sleep duration are associated with several human diseases, particularly obesity and type 2 diabetes, but until recently, little was known about the genetic factors influencing these heritable traits. We performed genome-wide association studies of self-reported chronotype (morning/evening person) and self-reported sleep duration in 128,266 white British individuals from the UK Biobank study. Sixteen variants were associated with chronotype (P<5x10-8), including variants near the known circadian rhythm genes RGS16 (1.21 odds of morningness, 95% CI [1.15, 1.27], P = 3x10-12) and PER2 (1.09 odds of morningness, 95% CI [1.06, 1.12], P = 4x10-10). The PER2 signal has previously been associated with iris function. We sought replication using self-reported data from 89,283 23andMe participants; thirteen of the chronotype signals remained associated at P<5x10-8 on meta-analysis and eleven of these reached P<0.05 in the same direction in the 23andMe study. We also replicated 9 additional variants identified when the 23andMe study was used as a discovery GWAS of chronotype (all P<0.05 and meta-analysis P<5x10-8). For sleep duration, we replicated one known signal in PAX8 (2.6 minutes per allele, 95% CI [1.9, 3.2], P = 5.7x10-16) and identified and replicated two novel associations at VRK2 (2.0 minutes per allele, 95% CI [1.3, 2.7], P = 1.2x10-9; and 1.6 minutes per allele, 95% CI [1.1, 2.2], P = 7.6x10-9). Although we found genetic correlation between chronotype and BMI (rG = 0.056, P = 0.05); undersleeping and BMI (rG = 0.147, P = 1x10-5) and oversleeping and BMI (rG = 0.097, P = 0.04), Mendelian Randomisation analyses, with limited power, provided no consistent evidence of causal associations between BMI or type 2 diabetes and chronotype or sleep duration. Our study brings the total number of loci associated with chronotype to 22 and with sleep duration to three, and provides new insights into the biology of sleep and circadian rhythms in humans.
Pub.: 06 Aug '16, Pinned: 27 Apr '17
Abstract: BackgroundChronotype has been related to obesity and metabolic disturbances. However, little is known about the relationship between circadian preferences and genetic background in CLOCK genes with obesity and weight loss among severe obese patients after bariatric surgery.ObjectiveThe research goals were (1) to examine whether evening chronotype is related to obesity and weight loss evolution in severe obese followed during six years after bariatric surgery and (2) to examine potential interactions between circadian preferences and CLOCK 3111T/C for obesity in this population.Subjects/MethodsParticipants (n=252, 79% female; age [mean+/-s.d.]: 52±11 years; BMI: 46.4±6.0 kg/m(2)) were grouped in evening-type and morning-types. Obesity and weight loss parameters, energy and macronutrients intake, energy expenditure, chronotype, meal timing, sleep duration, and CLOCK genotype were studied.ResultsEvening-type subjects showed significantly higher initial body weight (P=0.015) and BMI (P=0.014) than morning-types. Moreover, evening-type, when compared with morning-types, lost less weight (% of excess weight loss) after bariatric surgery (P=0.015). Weight-loss progression between the two chronotype groups differed significantly from the 4th year after the bariatric surgery towards a higher weight regain among evening-types (P<0.05). We also detected a significant interaction between CLOCK 3111T/C SNP and chronotype for body weight at baseline (P<0.001). Specifically, among carriers of the risk allele C, evening-types showed higher body weight than morning types (P=0.012). In addition, CLOCK 3111T/C SNP significantly associated with obesity and sleep duration in the older subjects.ConclusionsEvening chronotype is associated with higher obesity in severe obese subjects and with lower weight loss effectiveness after bariatric surgery. In addition, circadian preferences interact with CLOCK 3111T/C for obesity. The circadian and genetic assessment could provide tailored weight loss recommendations in subjects that underwent bariatric surgery.International Journal of Obesity accepted article preview online, 24 June 2016. doi:10.1038/ijo.2016.116.
Pub.: 25 Jun '16, Pinned: 27 Apr '17
Abstract: The circadian system is a supraphysiological system that modulates different biological functions such as metabolism, sleep-wake, cellular proliferation, and body temperature. Different chronodisruptors have been identified, such as shift work, feeding time, long days, and stress. The environmental changes and our modern lifestyle can alter the circadian system and increase the risk of developing pathologies such as cancer, preeclampsia, diabetes, and mood disorder. This system is organized by transcriptional/tranductional feedback loops of clock genes Clock, Bmal1, Per1-3, and Cry1-2. How molecular components of the clock are able to influence the development of diseases and their risk relation with genetic components of polymorphism of clock genes is unknown. This research describes different genetic variations in the population and how these are associated with risk of cancer, metabolic diseases such as diabetes, obesity, and dyslipidemias, and also mood disorders such as depression, bipolar disease, excessive alcohol intake, and infertility. Finally, these findings will need to be implemented and evaluated at the level of genetic interaction and how the environment factors trigger the expression of these pathologies will be examined.
Pub.: 18 Jun '16, Pinned: 27 Apr '17
Abstract: The purpose of this study was to find genes linked with eating disorders and associated with both metabolic and neural systems. Our operating hypothesis was that there are genetic factors underlying some eating disorders resting in both those pathways. Specifically, we are interested in disorders that may rest in both sleep and metabolic function, generally called Night Eating Syndrome (NES). A meta-analysis of the Gene Expression Omnibus targeting the mammalian nervous system, sleep, and obesity studies was performed, yielding numerous genes of interest. Through a text-based analysis of the results, a number of potential candidate genes were identified. VGF, in particular, appeared to be relevant both to obesity and, broadly, to brain or neural development. VGF is a highly connected protein that interacts with numerous targets via proteolytically digested peptides. We examined VGF from an evolutionary perspective to determine whether other available evidence supported a role for the gene in human disease. We conclude that some of the already identified variants in VGF from human polymorphism studies may contribute to eating disorders and obesity. Our data suggest that there is enough evidence to warrant eGWAS and GWAS analysis of these genes in NES patients in a case-control study.
Pub.: 19 Apr '16, Pinned: 27 Apr '17
Abstract: Obesity is a multifactorial disease caused by the interaction of genetic and environmental factors related to lifestyle aspects. It has been shown that reduced sleep is associated with increased body mass index (BMI). Circadian Locomotor Output Cycles Kaput (CLOCK) gene variants have also been associated with obesity. The objective of this mini-review was to discuss the available literature related to CLOCK gene variants associated with adiposity and sleep duration in humans. In total, 16 articles complied with the terms of the search that reported CLOCK variants associated with sleep duration, energy intake, and BMI. Overall, six CLOCK single nucleotide polymorphisms (SNPs) have been associated with sleep duration, and three variants have been associated with energy intake variables. Overall, the most studied area has been the association of CLOCK gene with obesity; close to eight common variants have been associated with obesity. The most studied CLOCK SNP in different populations is rs1801260, and most of these populations correspond to European populations. Collectively, identifying at risk CLOCK genotypes is a new area of research that may help identify individuals who are more susceptible to overeating and gaining weight when exposed to short sleep durations.
Pub.: 11 Nov '15, Pinned: 27 Apr '17
Abstract: Short sleep duration has been associated with greater risks of obesity, hypertension, diabetes, and cardiovascular disease. Also, common genetic variants in the human Circadian Locomotor Output Cycles Kaput (CLOCK) show associations with ghrelin and total energy intake.We examined associations between habitual sleep duration, body mass index (BMI), and macronutrient intake and assessed whether CLOCK variants modify these associations.We conducted inverse-variance weighted, fixed-effect meta-analyses of results of adjusted associations of sleep duration and BMI and macronutrient intake as percentages of total energy as well as interactions with CLOCK variants from 9 cohort studies including up to 14,906 participants of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium.We observed a significant association between sleep duration and lower BMI (β ± SE = 0.16 ± 0.04, P < 0.0001) in the overall sample; however, associations between sleep duration and relative macronutrient intake were evident in age- and sex-stratified analyses only. We observed a significant association between sleep duration and lower saturated fatty acid intake in younger (aged 20-64 y) adults (men: 0.11 ± 0.06%, P = 0.03; women: 0.10 ± 0.05%, P = 0.04) and with lower carbohydrate (-0.31 ± 0.12%, P < 0.01), higher total fat (0.18 ± 0.09%, P = 0.05), and higher PUFA (0.05 ± 0.02%, P = 0.02) intakes in older (aged 65-80 y) women. In addition, the following 2 nominally significant interactions were observed: between sleep duration and rs12649507 on PUFA intake and between sleep duration and rs6858749 on protein intake.Our results indicate that longer habitual sleep duration is associated with lower BMI and age- and sex-specific favorable dietary behaviors. Differences in the relative intake of specific macronutrients associated with short sleep duration could, at least in part, explain previously reported associations between short sleep duration and chronic metabolic abnormalities. In addition, the influence of obesity-associated CLOCK variants on the association between sleep duration and macronutrient intake suggests that longer habitual sleep duration could ameliorate the genetic predisposition to obesity via a favorable dietary profile.
Pub.: 21 Dec '14, Pinned: 27 Apr '17
Abstract: Prader-Willi syndrome (PWS), a genetic disorder of obesity, intellectual disability and sleep abnormalities, is caused by loss of non-coding RNAs on paternal chromosome 15q11-q13. The imprinted minimal PWS locus encompasses a long non-coding RNA (lncRNA) transcript processed into multiple SNORD116 small nucleolar RNAs and the spliced exons of the host gene, 116HG. However, both the molecular function and the disease relevance of the spliced lncRNA 116HG are unknown. Here, we show that 116HG forms a subnuclear RNA cloud that co-purifies with the transcriptional activator RBBP5 and active metabolic genes, remains tethered to the site of its transcription and increases in size in post-natal neurons and during sleep. Snord116del mice lacking 116HG exhibited increased energy expenditure corresponding to the dysregulation of diurnally expressed Mtor and circadian genes Clock, Cry1 and Per2. These combined genomic and metabolic analyses demonstrate that 116HG regulates the diurnal energy expenditure of the brain. These novel molecular insights into the energy imbalance in PWS should lead to improved therapies and understanding of lncRNA roles in complex neurodevelopmental and metabolic disorders.
Pub.: 19 Jun '13, Pinned: 27 Apr '17
Abstract: Genetics is behind our circadian machinery. CLOCK (Circadian Locomotor Output Cycles Kaput) 3111T/C single-nucleotide polymorphism (SNP) has been previously related to obesity and weight loss. However, phenotypic association and functionality of CLOCK 3111 locus is still unknown. The aim of this study was to determine, in free-living conditions, if the presence of CLOCK 3111C in overweight women could be related to (a) circadian disorders, and (b) changes in sleep quality, to improve understanding of the previously demonstrated associations with obesity and reduced weight loss of the C carriers.Wrist temperature, actimetry and position (TAP) and TAP variables were measured as markers of circadian functionality during 8 consecutive days. A rest-activity and food diary was also completed, whereas sleep quality was determined by domiciliary polysomnography. We recruited 85 women who were overweight with body mass index (BMI) of 28.59±4.30 kg m(-2) and age 43±12 years. From this sample, we found that 43 women were carrying the minor allele (C) for CLOCK 3111T/C SNP and 42 women were TT carriers (major allele carriers). Both groups of patients were matched for number, age, obesity parameters and energy intake.Compared with TT subjects, who showed more robust circadian rhythm profiles, patients with the C allele displayed significant circadian abnormalities: lower amplitude and greater fragmentation of the rhythm, a less stable circadian pattern and a significantly weakened circadian function, as assessed by the circadian function index (CFI). C subjects were also less active, started their activities later in the morning and were sleepier during the day, showing a delayed acrophase that characterizes 'evening-type' subjects.C genetic variants in CLOCK 3111T/C display a less robust circadian rhythm than TT and a delayed acrophase that characterizes 'evening-type' subjects. We support the notion that identifying CLOCK genotypes in patients may assist the therapist in characterization of the roots of the metabolic problem.
Pub.: 28 Nov '12, Pinned: 27 Apr '17