The genetics of obesity: from discovery to biology.

The prevalence of obesity has tripled over the past four decades, imposing an enormous burden on people's health. Polygenic (or common) obesity and rare, severe, early-onset monogenic obesity are often polarized as distinct diseases. However, gene discovery studies for both forms of obesity show that they have shared genetic and biological underpinnings, pointing to a key role for the brain in the control of body weight. Genome-wide association studies (GWAS) with increasing sample sizes and advances in sequencing technology are the main drivers behind a recent flurry of new discoveries. However, it is the post-GWAS, cross-disciplinary collaborations, which combine new omics technologies and analytical approaches, that have started to facilitate translation of genetic loci into meaningful biology and new avenues for treatment

Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10−6 in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10−8) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health

MTNR1B rs10830963 is associated with fasting plasma glucose, HbA1C and impaired beta-cell function in Chinese Hans from Shanghai.

BACKGROUND: Genome-wide association studies (GWAS) in White Europeans have shown that genetic variation rs10830963 in melatonin receptor 1B gene (MTNR1B) is associated with fasting glucose and type 2 diabetes, which has also been replicated in several Asian populations. As a variant in the gene involved in the regulation of circadian rhythms, the effect of the variant on sleep status remains unknown. This study aimed to investigate the effects of MTNR1B rs10830963 on fasting glucose, type 2 diabetes and sleep status in Chinese Hans. METHODS: MTNR1B rs10830963 was genotyped in a population-based cohort including 3,210 unrelated Chinese Hans from Beijing and Shanghai, and tested for associations with risk of type 2 diabetes, diabetes-related traits and sleep status. RESULTS: We confirmed the associations of MTNR1B rs10830963 with fasting glucose (beta = 0.11 mmol/l, 95%CI [0.03, 0.18], P = 0.005), glycated hemoglobin (HbA1c) (beta = 0.07%, 95%CI [0.02,0.12], P = 0.004) and homeostasis model assessment of beta-cell function (HOMA-B) (beta = -5.01%, 95%CI [-8.24,-1.77], P = 0.003) in the Shanghai, but not in the Beijing subpopulation (P >or= 0.58). The effect size of MTNR1B rs10830963 on fasting glucose in Shanghai Chinese Hans was comparable to that reported from other Asian populations. We found no evidence of associations with type 2 diabetes (OR 1.05 [0.90-1.23], P = 0.54), homeostasis model assessment of insulin sensitivity (HOMA-S) (P = 0.86) or sleep status (P >or= 0.44). CONCLUSIONS: A common variant in MTNR1B was associated with fasting glucose, HbA1C and HOMA-B but not with sleep status in Chinese Hans from Shanghai, strengthening the role of MTNR1B rs10830963 in fasting glycemia and impaired beta-cell function.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Blood pressure in young adulthood and residential greenness in the early-life environment of twins

Background: Previous research shows that, besides risk factors in adult life, the early-life environment can influence blood pressure and hypertension in adults. However, the effects of residential traffic exposure and residential greenness in the early-life on blood pressure in young adulthood are currently unknown. Methods: Ambulatory (24-h) blood pressures of 278 twins (132 pairs) of the East Flanders Prospective Twins Study were obtained at the age of 18 to 25 years. Prenatal and adulthood residential addresses were geocoded and used to assign prenatal and postnatal traffic and greenness indicators. Mixed modelling was performed to investigate blood pressure in association with greenness while adjusting for potential confounding factors. Results: Night-time systolic blood pressure was inversely associated with greenness at the residential address in twins living at the same address their entire life (non-movers, n = 97, 34.9%). An interquartile increase in residential greenness exposure (1000 m radius) was associated with a 3.59 mmHg (95% CI: -6.0 to -1.23; p = 0.005) lower adult night systolic blood pressure. Among twins who were living at a different address than their birth address at time of the measurement (n = 181, 65.1%), night-time blood pressure was inversely associated with residential surrounding greenness at adult age as well as with residential greenness in early-life. However after additional adjustment for residential greenness exposure in adulthood, only residential greenness exposure in early-life was significantly associated with night systolic blood pressure. While no significant effect of adult residential greenness with adult blood pressure was observed, while accounting for the early-life greenness exposure. Conclusions: Lower residential greenness in the early-life environment was independently associated with a higher adult blood pressure. This indicates that residential greenness has persistent effects on blood pressure

Persistent thinness and anorexia nervosa differ on a genomic level

Thinness and anorexia nervosa are both characterised by persistent low weight. Individuals with anorexia nervosa concurrently report distorted perceptions of their body and engage in weight-loss behaviours, whereas individuals with thinness often wish to gain weight. Both conditions are heritable and share genomics with BMI, but are not genetically correlated with each other. Based on their pattern of genetic associations with other traits, we explored differences between thinness and anorexia nervosa on a genomic level. In Part 1, using publicly available data, we compared genetic correlations of persistent thinness/anorexia nervosa with eleven psychiatric disorders. In Part 2, we identified individuals with adolescent persistent thinness in the Avon Longitudinal Study of Parents and Children (ALSPAC) by latent class growth analysis of measured BMI from 10 to 24 years (n = 6594) and evaluated associations with psychiatric and anthropometric polygenic scores. In Part 1, in contrast to the positive genetic correlations of anorexia nervosa with various psychiatric disorders, persistent thinness showed negative genetic correlations with attention deficit hyperactivity disorder (r gAN = 0.08 vs. r gPT = −0.30), alcohol dependence (r gAN = 0.07 vs. r gPT = −0.44), major depressive disorder (rgAN = 0.27 vs. rgPT = −0.18) and post-traumatic stress disorder (rgAN = 0.26 vs. rgPT = −0.20). In Part 2, individuals with adolescent persistent thinness in the ALSPAC had lower borderline personality disorder polygenic scores (OR = 0.77; Q = 0.01). Overall, results suggest that genetic variants associated with thinness are negatively associated with psychiatric disorders and therefore thinness may be differentiable from anorexia nervosa on a genomic level

Common Genetic Determinants of Glucose Homeostasis in Healthy Children: The European Youth Heart Study

OBJECTIVE-The goal of this study was to investigate whether the effects of common genetic variants associated with fasting glucose in adults are detectable in healthy children.RESEARCH DESIGN AND METHODS-Single nucleotide polymorphisms in MTNR1B (rs10830963), G6PC2 (rs560887), and GCK (rs4607517) were genotyped in 2,025 healthy European children aged 9-11 and 14-16 years. Associations with fasting glucose, insulin, homeostasis model assessment (HOMA)-insulin resistance (IR) and HOMA-B were investigated along with those observed for type 2 diabetes variants available in this study (CDKN2A/B, IGF2BP2, CDKAL1, SLC30A8, HHEX-IDE, and Chr 11p12).RESULTS-Strongest associations were observed for G6PC2 and MTNR1B, with mean fasting glucose levels (95% Cl) being 0.084 (0.06-0.11) mmol/l, P = 7.9 x 10(-11) and 0.069 (0.04-0.09) mmol/l, p = 1.9 x 10(-7) higher per risk allele copy, respectively. A similar but weaker trend was observed for GCK (0.028 [-0.006 to 0.06] mmol/l, P = 0.11). All three variants were associated with lower P-cell function (HOMA-B P = 9.38 x 10(-5), 0.004, and 0.04, respectively). SLC30A8 (rs13266634) was the only type 2 diabetes variant associated with higher fasting glucose (0.033 mmol/l [0.01-0.06], P = 0.01). Calculating a genetic predisposition score adding the number of risk alleles of G6PC2, MTNR1B, GCK, and SLC30A8 showed that glucose levels were successively higher in children carrying a greater number of risk alleles (P = 7.1 x 10(-17)), with mean levels of 5.34 versus 4.91 mmol/l comparing children with seven alleles (0.6% of all children) to those with none (0.5%). No associations were found for fasting insulin or HOMA-IR with any of the variants.CONCLUSIONS-The effects of common polymorphisms influencing fasting glucose are apparent in healthy children, whereas the presence of multiple risk alleles amounts to a difference of >1 SD of fasting glucose. Diabetes 58:2939-2945, 200

The Contribution of Prenatal Environment and Genetic Factors to the Association between Birth Weight and Adult Grip Strength

Low birth weight has been associated with reduced hand grip strength, which is a marker of future physical function and disease risk. The aim of this study was to apply a twin pair approach, using both ‘individual’ data and ‘within-pair’ differences, to investigate the influence of birth weight on hand grip strength and whether this association may be mediated through fat free mass (FFM). Participants from the East Flanders Prospective Twin Survey were included if born without congenital abnormalities, birth weight >500 g and ≥22 weeks of gestation. Follow up in adulthood (age: 18–34 year), included anthropometric measures and hand grip (n = 783 individuals, n = 326 same-sex twin pairs). Birth weight was positively associated with hand grip strength (β = 2.60 kg, 95% CI 1.52, 3.67, p<0.001) and FFM (β = 4.2, 95% CI 3.16, 5.24, p<0.001), adjusted for gestational age, sex and adult age. Using ‘within-pair’ analyses, the birth weight hand grip association was significant in DZ men only (β = 5.82, 95% CI 0.67, 10.97, p = 0.028), which was attenuated following adjustment for FFM. Within-pair birth weight FFM associations were most pronounced in DZ men (β = 11.20, 95% CI 7.18, 15.22, p<0.001). Our ‘individual’ analyses show that higher birth weight is associated with greater adult hand grip strength, which is mediated through greater adult FFM. The ‘within-pair’ analyses confirm this observation and furthermore show that, particularly in men, genetic factors may in part explain this association, as birth weight differences in DZ men result in greater differences in adult strength and FFM

Körperproportionen der Leistungsstärkstenjuniorenruderer im bezug auf Wettkampfniveau,den Stil des Ruderns und die Bootsgattung

The performance of elite rowers is, beside others, determined by their physical characteristics. Anthropometric data for adult rowers emphasise the importance of body mass and body size for rowing performance. Little is known concerning the importance of proportional length development. At the 1997 World Junior Rowing Championships anthropometric measurements (body mass and 6 length dimensions) were performed on 383 elite male junior rowers. Based on these measurements several proportional length dimensions were calculated. Data on boat type were obtained by questionnaire and data on competition level were based on the results obtained during the championship. The results indicate that these rowers were heavier (Mean = 82.2±7.4 kg) and taller (Mean = 187.4±5.8 cm) and had a larger sitting height (Mean=96.8±3.2 cm) and longer legs (Mean= 90.7±3.8 cm) than a reference population. Finalists had significantly larger length dimensions than non-finalists and sweep rowers had in general larger length dimensions than scullers. No differences existed when the length dimensions were expressed proportional to the stature of the rowers. It can be concluded that elite junior rowers have larger length dimensions compared to less successful rowers, but these top athletes do not differentiate from the sub-elite athletes regarding proportional length development. Differences could be observed between sweep rowers and scullers with larger length dimensions in favour of sweep rowers.Uvod Natjecateljska uspješnost vrhunskih veslača određena je, između ostaloga, i njihovim tjelesnim karakteristikama. S biološkog stajališta možemo kod sportaša olimpijske i svjetske razine kvalitete očekivati optimalnu ekspresiju utjecaja nasljeđa, sportske pripreme, prehrane i socio-kulturnih faktora. Ispitivanje obilježja tih sportaša može pomoći kineziolozima, znanstvenicima i trenerima, u razumijevanju vrhunskog sportskog uspjeha time što im pruža informacije korisne za oblikovanje strategija za objašnjenje i predviđanje sportskih rezultata. U prošlosti su se antropometrijske studije bavile uglavnom veslačima seniorima, a manje juniorima. Te antropometrijske studije naglašavaju važnost tjelesne mase i veličine tijela za uspješnost u veslanju. Smatra se da osobitu prednost veslačima donose duži udovi zbog toga što su to duže poluge i što omogućuju veću radnu snagu. Duge noge pojačavaju potisnu fazu (provlak) veslačkog zaveslaja. Štoviše, veći veslači imaju veći presjek mišića i veći apsolutni energetski kapacitet. Proučavanje longitudinalnih dimenzija do sada je bilo uglavnom ograničeno na varijablu “visina tijela ili stas”. Samo je nekoliko studija o proporcijama longitudinalnih dimenzija vrhunskih veslača, pa se malo zna o važnosti longitudinalnih proporcija tijela veslača. Cilj je ove studije bio trostruk: (1) opisati razvojne proporcijske longitudinalne dimenzije juniora veslača u usporedbi s flamanskim mladićima, (2) usporediti tjelesne proporcije veslača prema različitim kvalitetnim natjecateljskim razinama, načinu veslanja i kategorijama čamca i (3) ustanoviti model antropometrijskog profila za veslače juniore. Metode Uzorak ispitanika činila su 383 veslača juniora, u dobi od 17,8 ± 0,7 godina, raspon godina od 15,1 do 18,6. Ispitanici su nastupili na FISA svjetskom ju-niorskom veslačkom prvenstvu 1997 godine. Istraživanjem je obuhvaćeno 90% sudionika (bez kormilara), od toga 83% pobjednika i osvajača meda-lja te 89% finalista. Svi su trenirali 7-10 puta tjedno (10-15 sati). Potpuni opis uzorka i mjerenja može se naći u članku Bourgois i suradnici (1998). Za ovaj članak upotrijebljene su sljedeće tjelesne dimenzije: tjelesna visina, sjedeća visina, duljina nadlaktice, duljina podlaktice, duljina šake i duljina potkoljenice. Mjerenja su provedena u standardnim uvjetima prema postupcima koje su opisali Claessens i suradnici (1998). Na temelju tih mjera izračunate su proporcijske longitudinalne dimenzije. Pregled varijabli prikazan je u tablici 1. Podaci o vrsti čamca prikupljeni su upitnikom, a podaci o kvalitetnoj razini temeljili su se na rezultatima postignutima na prvenstvu. Međunarodna juniorska veslačka natjecanja standardizirana su na stazi od 2 000 m i podijeljena su u discipline veslanja jednim veslom (rimen) i veslanja na pariće (skul). Te se veslačke tehnike međusobno dosta razlikuju – veslač u čamcu rimen, dakle, vesla samo jednim veslom, dok skuleri koriste dva kraća vesla koja povlače istodobno. Izračunati su parametri deskriptivne statistike (aritmetička sredina, standardna devijacija i raspon) za sve varijable i za ukupni uzorak veslača. Za usporedbu proporcijskih odnosa između rimen veslača i skul veslača te finalista i onih koji se nisu plasirali u finale upotrijebljen je Studentov t-test za nezavisne uzorke. Analiza varijance (ANOVA) i post-hoc Tukeyjev test primijenjeni su da bi se otkrile razlike u proporcionalnosti među veslačima u raznim vrstama čamaca. Za statističke analize korišten je računalni program Statistical Analysis System. Svi su testovi bili dvostruki, a značajnom se smatrala razlika na razini od p<0.05. Rezultati Deskriptivna statistika prikazana je u tablici 3. U tablici su uspoređene proporcije veslača u rimenu i skulu. Rimen veslači bili su značajno viši i teži od skulera. Kada su se longitudinalne dimenzije dovele u proporcijski odnos prema tjelesnoj visini, nisu primijećene značajne razlike između te dvije vrste veslača. Slični su se rezultati dobili i u usporedbi finalista i ne-finalista (tablica 5). Prema rezultatima analize varijance (tablica 6) razlike između dva stila veslanja (rimen nasuprot skul) nađene su između dvojca sa (2+) i četverca sa (4+), s jedne strane, te samca (1x), četverca na pariće (4x) i dvojca bez (2-), s druge strane. Sportaši koji veslaju u dvojcu sa (2+) i četvercu sa (4+) bili su, u prosjeku, teži i viši od veslača u samcu (1x), četvercu na pariće (4x) i dvojcu bez (2-). Nisu dobivene razlike u proporcijskim odnosima longitudinalnih dimenzija prema vrsti čamaca. U tablici 7 predstavljen je model profila proporcijskih odnosa longitudinalnih dimenzija za veslače juniore koji su nastupili na FISA svjetskom juniorskom veslačkom prvenstvu. Rasprava i zaključak Rezultati pokazuju da su promatrani veslači teži i viši te da imaju veću sjedeću visinu i duže noge od opće populacije. Finalisti su imali značajno veće longitudinalne dimenzije od ne-finalista, a rimen veslači su općenito imali veće longitudinalne dimenzije od skulera. Nisu, međutim, dobivene razlike kada su longitudinalne dimenzije postavljene u proporcijski odnos prema tjelesnoj visini. Veslanje je sport izdržljivosti i longitudinalne dimenzije su nedvojbeno povezane s uspješnošću. Duge noge pojačavaju potisak u fazi provlaka tijekom veslačkog zaveslaja, što znači da su veslači s dugim nogama u biomehaničkoj prednosti. Usporedba tjelesnih proporcija izmjerenih veslača juniora s vrijednostima o kojima su izvijestili drugi autori (Carter i dr., 1982; Rodriguez, 1986) otkriva da veslači juniori imaju manju sjedeću visinu u odnosu na ukupnu tjelesnu visinu ili stas (Valoisov indeks) (51,6%) i veću duljinu nogu u odnosu na stas (48,4%) od normativne usporedne skupine (Ostyn i dr., 1980) (52,1% i 47,9%) i od teških olimpijskih veslača (Carter i dr, 1982) (52,1% i 47,.9%). Nisu dobivene razlike između veslača juniora i vrhunskih lakih veslača (51,5% i 48,5%). Može se zaključiti da su kvalitetniji veslači uglavnom viši i, povezano s tom razlikom, imaju veće longitudinalne dimenzije od manje uspješnih veslača, ali se oni ne razlikuju međusobno kada se te vrijednosti izraze proporcionalno u odnosu na njihovu tjelesnu visinu. Uočene su razlike između rimen veslača i skul veslača – rimen veslači su višega stasa i imaju veće apsolutne vrijednosti longitudinalnih dimenzija. Uz to što je izrađen profil veslača juniora, rezultati ove studije mogu pomoći trenerima i kineziolozima da steknu bolji uvid u to koje su morfološke karakteristike povezane s uspješnošću u veslanju. Rezultati se također mogu primijeniti za određenje antropometrijskog profila veslača i kao instrument za selekciju dječaka talentiranih za veslanje.Die Leistung der leistungsstärksten Ruderer ist unter anderem von ihren körperlichen Eigenschaften bestimmt. Körperbaudaten für erwachsene Ruderer stellen den Nachdruck auf die Wichtigkeit des Körpergewichts und der Körperhöhe für das Rudern. Es bleibt noch unklar, wie wichtig die proportionale Längenzunahme ist. Während der Junioren Weltmeisterschaften im 1997 wurden die Körperbau-Messungen (Körpergewicht und 6 Extremitätenlängen) auf 383 leistungsstärksten Junioren-Ruderer vorgenommen. Auf Grund dieser Messungen einige proportionale Extremitätenlängen wurden berechnet. Die Angaben über die Bootsgat-tung wurden einem Fragebogen entnommen, während die Angaben über dem Wettkampf-Niveau auf den während der Meisterschaft gewonnenen Ergebnissen basierten. Den Ergebnissen nach wogen diese Ruderer mehr (Mittelwert = 82,2±7,4 kg), sie waren größer (Mittelwert = 187,4±5,8 cm) und hatten eine größere Sitzhöhe (Mittelwert = 96,8±3,2 cm) und längere Beine (Mittelwert = 90,7±3,8 cm) als die Referenz-Grundgesamtheit. Die Finalisten hatten bedeutend größere Extremitätenlängenwerte als die Nicht-Finalisten, während die Riemenruderer im allgemeinen größere Extremitätenlängenwerte hatten als die Skuller. Keine Unterschiede waren zu merken, wenn die Extremitätenlängenwerte proportional der Körperhöhe der Ruderer dargestellt wurden. Daraus lässt sich schließen, dass die leistungsstärksten Junioren größere Extremitätenlängenwerte haben im Vergleich zu den weniger erfolgreichen Ruderern, aber diese Spitzensportler unterscheiden sich keineswegs von weniger erfolgreichen Sportlern im Bezug auf die proportionale Längenzunahme. Die Unterschiede sind bei den Riemenruderern und den Skullern zu merken, wobei die Skuller größere Extremitätenlängenwerte aufzeigen

Life course variations in the associations between FTO and MC4R gene variants and body size

The timing of associations between common genetic variants for weight or body mass index (BMI) across the life course may provide insights into the aetiology of obesity. We genotyped variants in FTO (rs9939609) and near MC4R (rs17782313) in 1240 men and 1239 women born in 1946 and participating in the MRC National Survey of Health and Development. Birth weight was recorded and height and weight were measured or self-reported repeatedly at 11 time-points between ages 2 and 53 years. Hierarchical mixed models were used to test whether genetic associations with weight or BMI standard deviation scores (SDS) changed with age during childhood and adolescence (2–20 years) or adulthood (20–53 years). The association between FTO rs9939609 and BMI SDS strengthened during childhood and adolescence (rate of change: 0.007 SDS/A-allele/year; 95% CI: 0.003–0.010, P < 0.001), reached a peak strength at age 20 years (0.13 SDS/A-allele, 0.08–0.19), and then weakened during adulthood (−0.003 SDS/A-allele/year, −0.005 to −0.001, P = 0.001). MC4R rs17782313 showed stronger associations with weight than BMI; its association with weight strengthened during childhood and adolescence (0.005 SDS/C-allele/year; 0.001–0.008, P = 0.006), peaked at age 20 years (0.13 SDS/C-allele, 0.07–0.18), and weakened during adulthood (−0.002 SDS/C-allele/year, −0.004 to 0.000, P = 0.05). In conclusion, genetic variants in FTO and MC4R showed similar biphasic changes in their associations with BMI and weight, respectively, strengthening during childhood up to age 20 years and then weakening with increasing adult age. Studies of the aetiology of obesity spanning different age groups may identify age-specific determinants of weight gain

Citrullination of Epithelial Neutrophil–Activating Peptide 78/CXCL5 Results in Conversion From a Non–Monocyte‐Recruiting Chemokine to a Monocyte‐Recruiting Chemokine

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108594/1/art38750.pd