Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people.

The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 × 10-8) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits.

Prenatal exposure to cigarette smoke interacts with OPRM1 to modulate dietary preference for fat.

BACKGROUND: Preference for fatty foods is a risk factor for obesity. It is a complex behaviour that involves the brain reward system and is regulated by genetic and environmental factors, such as the opioid receptor mu-1 gene (OPRM1) and prenatal exposure to maternal cigarette smoking (PEMCS). We examined whether OPRM1 and PEMCS interact in influencing fat intake and whether exposure-associated epigenetic modifications of OPRM1 may mediate this gene-environment interaction. METHODS: We studied adolescents from a French Canadian genetic founder population, half of whom were exposed prenatally to maternal cigarette smoking. Fat intake was assessed with a 24-hour food recall in the form of a structured interview conducted by a trained nutritionist. The OPRM1 variant rs2281617 was genotyped for the whole sample with the Illumina Human610-Quad and HumanOmniExpress BeadChips. Methylation of blood DNA was assessed at 21 CpGs across OPRM1 in a subset of the sample using the Illumina HumanMethylation450 BeadChip. RESULTS: We included 956 adolescents in our study. In the whole sample, OPRM1 (T carrier in rs2281617) was associated with lower fat intake (-1.6%, p = 0.017), and PEMCS was associated with higher fat intake (+1.6%, p = 0.005). OPRM1 and PEMCS interacted with each other (p = 0.003); the "protective" (fat intake-lowering) allele of OPRM1 was associated with lower fat intake in nonexposed (-3.2%, p < 0.001) but not in exposed individuals (+0.8%, p = 0.42). Further, PEMCS was associated with lower DNA methylation across multiple CpGs across OPRM1 in exposed versus nonexposed individuals (p = 0.031). LIMITATIONS: A limitation of our study was its cross-sectional design. CONCLUSION: Our study suggests that PEMCS may interact with OPRM1 in increasing fat preference. Silencing of the protective OPRM1 allele in exposed adolescents might be related to epigenetic modification of this gene.

Clustering of the metabolic syndrome components in adolescence: role of visceral fat.

Visceral fat (VF) promotes the development of metabolic syndrome (MetS), which emerges as early as in adolescence. The clustering of MetS components suggests shared etiologies, but these are largely unknown and may vary between males and females. Here, we investigated the latent structure of pre-clinical MetS in a community-based sample of 286 male and 312 female adolescents, assessing their abdominal adiposity (VF) directly with magnetic resonance imaging. Principal component analysis of the five MetS-defining variables (VF, blood pressure [BP], fasting serum triglycerides, HDL-cholesterol and glucose) identified two independent components in both males and females. The first component was sex-similar; it explained >30% of variance and was loaded by all but BP variables. The second component explained >20% of variance; it was loaded by BP similarly in both sexes but additional loading by metabolic variables was sex-specific. This sex-specificity was not detected in analyses that used waist circumference instead of VF. In adolescence, MetS-defining variables cluster into at least two sub-syndromes: (1) sex-similar metabolic abnormalities of obesity-induced insulin resistance and (2) sex-specific metabolic abnormalities associated with BP elevation. These results suggest that the etiology of MetS may involve more than one pathway and that some of the pathways may differ between males and females. Further, the sex-specific metabolic abnormalities associated with BP elevation suggest the need for sex-specific prevention and treatment strategies of MetS.

Routine clinical measures of adiposity as predictors of visceral fat in adolescence: a population-based magnetic resonance imaging study.

OBJECTIVE: Visceral fat (VF) increases cardiometabolic risk more than fat stored subcutaneously. Here, we investigated how well routine clinical measures of adiposity, namely body mass index (BMI) and waist circumference (waist), predict VF and subcutaneous fat (SF) in a large population-based sample of adolescents. As body-fat distribution differs between males and females, we performed these analyses separately in each sex. DESIGN AND METHODS: VF and SF were measured by magnetic resonance imaging in 1,002 adolescents (482 males, age 12-18 years). Relationships of BMI and waist with VF and SF were tested in multivariable analyses, which adjusted for potentially confounding effects of age and height. RESULTS: In both males and females, BMI and waist were highly correlated with VF and SF, and explained 55-76% of their total variance. When VF was adjusted for SF, however, BMI and waist explained, respectively, only 0% and 4% of VF variance in males, and 4% and 11% of VF variance in females. In contrast, when SF was adjusted for VF, BMI and waist explained, respectively, 36% and 21% of SF variance in males, and 48% and 23% of SF variance in females. These relationships were similar during early and late puberty. CONCLUSIONS AND RELEVANCE: During adolescence, routine clinical measures of adiposity predict well SF but not VF. This holds for both sexes and throughout puberty. Further longitudinal studies are required to assess how well these measures predict changes of VF and SF over time. Given the clinical importance of VF, development of cost-effective imaging techniques and/or robust biomarkers of VF accumulation that would be suitable in everyday clinical practice is warranted.

Prenatal exposure to maternal cigarette smoking, amygdala volume, and fat intake in adolescence.

CONTEXT: Prenatal exposure to maternal cigarette smoking is a well-established risk factor for obesity, but the underlying mechanisms are not known. Preference for fatty foods, regulated in part by the brain reward system, may contribute to the development of obesity. OBJECTIVE: To examine whether prenatal exposure to maternal cigarette smoking is associated with enhanced fat intake and risk for obesity, and whether these associations may be related to subtle structural variations in brain regions involved in reward processing. DESIGN: Cross-sectional study of a population-based cohort. SETTING: The Saguenay Youth Study, Quebec, Canada. PARTICIPANTS: A total of 378 adolescents (aged 13 to 19 years; Tanner stage 4 and 5 of sexual maturation), half of whom were exposed prenatally to maternal cigarette smoking (mean [SD], 11.1 [6.8] cigarettes/d). MAIN OUTCOME MEASURES: Fat intake was assessed with a 24-hour food recall (percentage of energy intake consumed as fat). Body adiposity was measured with anthropometry and multifrequency bioimpedance. Volumes of key brain structures involved in reward processing, namely the amygdala, nucleus accumbens, and orbitofrontal cortex, were measured with magnetic resonance imaging. RESULTS: Exposed vs nonexposed subjects exhibited a higher total body fat (by approximately 1.7 kg; P = .009) and fat intake (by 2.7%; P = .001). They also exhibited a lower volume of the amygdala (by 95 mm3; P < .001) but not of the other 2 brain structures. Consistent with its possible role in limiting fat intake, amygdala volume correlated inversely with fat intake (r = -0.15; P = .006). CONCLUSIONS: Prenatal exposure to maternal cigarette smoking may promote obesity by enhancing dietary preference for fat, and this effect may be mediated in part through subtle structural variations in the amygdala.

FTO, obesity and the adolescent brain.

Genetic variations in fat mass- and obesity (FTO)-associated gene, a well-replicated gene locus of obesity, appear to be associated also with reduced regional brain volumes in elderly. Here, we examined whether FTO is associated with total brain volume in adolescence, thus exploring possible developmental effects of FTO. We studied a population-based sample of 598 adolescents recruited from the French Canadian founder population in whom we measured brain volume by magnetic resonance imaging. Total fat mass was assessed with bioimpedance and body mass index was determined with anthropometry. Genotype-phenotype associations were tested with Merlin under an additive model. We found that the G allele of FTO (rs9930333) was associated with higher total body fat [TBF (P = 0.002) and lower brain volume (P = 0.005)]. The same allele was also associated with higher lean body mass (P = 0.03) and no difference in height (P = 0.99). Principal component analysis identified a shared inverse variance between the brain volume and TBF, which was associated with FTO at P = 5.5 × 10(-6). These results were replicated in two independent samples of 413 and 718 adolescents, and in a meta-analysis of all three samples (n = 1729 adolescents), FTO was associated with this shared inverse variance at P = 1.3 × 10(-9). Co-expression networks analysis supported the possibility that the underlying FTO effects may occur during embryogenesis. In conclusion, FTO is associated with shared inverse variance between body adiposity and brain volume, suggesting that this gene may exert inverse effects on adipose and brain tissues. Given the completion of the overall brain growth in early childhood, these effects may have their origins during early development.

Sex differences in the contributions of visceral and total body fat to blood pressure in adolescence.

Excess body fat deposited viscerally rather than elsewhere in the body is associated with higher risk for hypertension; this relationship is stronger in men than in women. Here we investigated whether similar sex dimorphism exists already in adolescence. A population-based sample of adolescent boys (n=237) and girls (n=262), age 12 to 18 years, was studied. Total body fat (TBF) was assessed with multifrequency bioelectrical impedance, and visceral fat (VF) was quantified with MRI. Blood pressure (BP) was measured beat by beat during an hour-long protocol, including supine, standing, sitting, mental stress, and poststress sections. Multivariate mixed-model analysis was used to assess the relative contributions of TBF and VF to BP during these sections. In boys, BP was strongly positively associated with VF (P<0.0001), whereas it was less strongly and negatively associated with TBF (P=0.004); these relationships did not substantially vary during the protocol. In contrast, in girls, BP was strongly positively associated with TBF (P=0.0006), whereas it was not associated with VF (P=0.08); the relationship with TBF varied during the protocol and was most apparent during mental stress (TBF*section interaction: P=0.002). Furthermore, when waist circumference was included in multivariate models instead of VF, it was not associated with BP in either sex; this indicates that waist circumference may not be an appropriate surrogate for VF. Thus, in adolescence, adiposity-related BP elevation is driven mainly by visceral fat in males and by fat deposited elsewhere in females. This dimorphism suggests sex-specific mechanisms of obesity-induced hypertension and the need for sex-specific criteria of its prevention.

Genome-wide scan for loci of adolescent obesity and their relationship with blood pressure.

CONTEXT: Hypertension, typically considered a disorder of adulthood, is now emerging in adolescence. This is mainly due to the growing prevalence of obesity and the fact that excess body fat increases blood pressure (BP). OBJECTIVE: The objective of the study was to investigate whether genome-wide identified gene loci of obesity are associated with elevated BP in adolescence. DESIGN: This was a genotype-phenotype association study. SETTING: The study was conducted in a French-Canadian founder population. PARTICIPANTS: Participants included 598 adolescents, aged 12-18 yr. INTERVENTION: Testing associations between 530,011 single-nucleotide polymorphisms (SNP; Human610W-Quad BeadChip) and obesity measures and between identified SNP and BP. PRIMARY OUTCOME MEASURES: Total fat mass (TFM) was assessed with bioelectrical impedance, and body mass index (BMI) was determined with anthropometry. BP was measured beat by beat during an hour-long protocol. RESULTS: The genome-wide association studies of TFM and BMI revealed two novel and several previously identified loci of obesity. The former were PAX5 (rs16933812, TFM: P = 9.3 × 10(-9)) and MRPS22 (rs7638110, BMI: P = 4.6 × 10(-8)), and the top ones among the latter (P < 5 × 10(-4)) were MC4R (rs17773430, BMI: P = 5.8 × 10(-6)), FTO (rs9930333, BMI: P = 1.9 × 10(-4)), and MTCH2 (rs7120548, BMI: P = 1.9 × 10(-4)). From these five, only the PAX5, MRPS22, and FTO were also associated with BP; their minor allele homozygotes vs. major allele homozygotes showed greater TFM by 2.9-8.0 kg and higher BP by 3.3-6.7 mm Hg. CONCLUSIONS: Genome-wide association studies conducted in an adolescent founder population revealed two new and a number of previously identified loci of obesity and demonstrated that several but not all of these loci are also associated with elevated BP. These results begin to reveal the genetic architecture of obesity-induced hypertension.

Functional variation in the androgen-receptor gene is associated with visceral adiposity and blood pressure in male adolescents.

Intra-abdominal accumulation of fat is a hallmark of male body-fat distribution and a major risk factor for hypertension. Sympathoactivation may be one of the mechanisms linking intra-abdominal obesity to hypertension. The aim of the present study was to investigate whether a functional variation in the androgen-receptor gene (AR, a variable number of CAG repeats in exon 1) is associated with intra-abdominal adiposity, sympathetic modulation of vasomotor tone, and blood pressure in adolescent boys but not girls. We studied 223 boys and 259 girls (age 12 to 18 years) from a French-Canadian founder population. Intra-abdominal fat and subcutaneous-abdominal fat were quantified with an MRI. Blood pressure was recorded beat-to-beat during an hour-long protocol including physical and mental challenges, and these blood pressure time series were used to assess sympathetic modulation of vasomotor tone by power spectral analysis. The results showed that boys with a "low" versus "intermediate" or "high" CAG-repeat number in AR demonstrated higher intra-abdominal fat (by 28% and 48%, respectively) but not subcutaneous-abdominal fat. These intra-abdominal fat differences remained significant after adjusting for serum levels of sex hormones and subcutaneous-abdominal fat. Furthermore, boys with low versus intermediate or high CAG-repeat numbers also showed higher blood pressure, with the differences being most pronounced during mental stress (8.0 and 8.5 mm Hg, respectively) and higher sympathetic modulation of vasomotor tone. As expected, no such differences were seen among girls. In adolescent boys, low CAG-repeat numbers in AR may be a genetic risk factor for intra-abdominal obesity and hypertension; sympathoactivation may be an underlying link between the 2 conditions.

Prenatal exposure to maternal cigarette smoking and accumulation of intra-abdominal fat during adolescence.

In industrialized countries, prenatal exposure to maternal cigarette smoking (PEMCS) is the most common environmental insult to the fetus. Here, we tested the hypothesis that PEMCS amplifies accumulation of abdominal fat during the accelerated weight gain occurring in late puberty. This hypothesis was tested in 508 adolescents (12-18 years, 237 exposed prenatally to maternal cigarette smoking) in whom subcutaneous and intra-abdominal fat were quantified with magnetic resonance imaging (MRI). We found that, in early puberty, exposed and nonexposed adolescents did not differ in MRI-based measures of adiposity. In late puberty, on the other hand, exposed compared with nonexposed adolescents demonstrated markedly higher quantities of both subcutaneous fat (by 26%, P = 0.004) and intra-abdominal fat (by 33%, P = 0.001). These group differences remained virtually unchanged after adjusting for sex and potential confounders, including birth weight and breastfeeding. As such, our results suggest that PEMCS may represent a major risk factor for the development of abdominal obesity at the later stages of puberty.

A common variant of the FTO gene is associated with not only increased adiposity but also elevated blood pressure in French Canadians.

BACKGROUND: FTO is the first gene established as contributing to common forms of obesity. The gene is highly expressed in the hypothalamus and is thought to mediate this effect through its influence on energy homeostasis. The hypothalamus, however, also regulates blood pressure (BP). Therefore, we investigated whether the FTO-risk variant is associated not only with increased adiposity but also with elevated BP and whether the latter may be mediated, in part, by increased sympathetic modulation of vasomotor tone. METHODS AND RESULTS: The primary study was carried out in 485 adolescents recruited from a French Canadian founder population who underwent detailed body-composition and cardiovascular phenotyping. Body fat was examined with MRI, bioimpedance, and anthropometry. BP was recorded beat to beat at rest and during physical and mental challenges. Sympathetic modulation of vasomotor tone was assessed with power spectral analysis of BP. We found that individuals with the FTO-risk genotype compared with those without it demonstrate greater adiposity, including the amount of intra-abdominal fat (by 38%). They also showed higher systolic BP throughout the entire protocol, with a maximum difference during a mental stress (6.4 [1.5 to 11.3] mm Hg). The difference in BP was accompanied by elevated index of sympathetic modulation of vasomotor tone. A replication in an independent sample of adults from the same founder population confirmed the association between FTO and BP. CONCLUSIONS: These results suggest that, in a French Canadian founder population, FTO may increase not only risk for obesity, as demonstrated in other populations, but also for hypertension. The latter may be related, at least in part, to the regulation of sympathetic vasomotor tone.

Sex differences in blood pressure and its relationship to body composition and metabolism in adolescence.

OBJECTIVES: To investigate during adolescence (1) sex differences in blood pressure (BP) and hemodynamic factors at rest and during physical and mental challenges and (2) whether these differences are mediated by body composition and glucose and lipid metabolism. DESIGN: Cross-sectional study of a population-based cohort. SETTING: Saguenay Youth Study, Quebec, Canada, from November 2003 to June 2007. PARTICIPANTS: A total of 425 adolescents (225 girls aged 12-18 years). OUTCOME MEASURES: Systolic and diastolic BP measured using a Finometer. Secondary outcome measures were (1) hemodynamic parameters also measured with a Finometer, (2) body composition assessed with magnetic resonance imaging, bioimpedance, and anthropometry, and (3) metabolic indices determined from a fasting blood sample. RESULTS: Girls vs boys demonstrated lower systolic and diastolic BP at rest and during challenges, with the differences being greatest during a math-stress test (adjusted difference, 7 mm Hg; 95% confidence interval [CI], 4-10 mm Hg and adjusted difference, 6 mm Hg; 95% CI, 4-8 mm Hg, respectively). The differences were mainly due to girls vs boys having lower stroke volume while lying down, standing (adjusted difference, 4 mL; 95% CI, 1-7 mL), and sitting, and lower total peripheral resistance during the math-stress test (adjusted difference, 0.14 mm Hg . s/mL; 95% CI, 0.09-0.21 mm Hg . s/mL). Intra-abdominal fat was positively associated with BP, but less in girls than in boys, and fat-free mass, fat mass, and insulin resistance were also positively associated with BP, similarly in boys and girls. CONCLUSIONS: In adolescence, BP is lower in girls than boys, with the difference being determined mainly by lower stroke volume during physical challenges and by lower total peripheral resistance during mental challenges. Body composition and insulin resistance contribute to these differences.

Intra-abdominal adiposity and individual components of the metabolic syndrome in adolescence: sex differences and underlying mechanisms.

OBJECTIVE: To investigate the association between intra-abdominal adiposity and individual components of the metabolic syndrome (MS) in adolescent males and females. DESIGN: Cross-sectional study of a population-based cohort. SETTING: Saguenay Youth Study, Quebec, Canada. PARTICIPANTS: A total of 324 adolescents, aged 12 to 18 years. INTERVENTION: Measures were compared between males and females with "high" or "low" intra-abdominal fat (IAF). MAIN OUTCOME MEASURES: Intra-abdominal fat was quantified with magnetic resonance imaging. Primary outcome measures were blood pressure (BP) and fasting serum glucose, insulin, lipids, and C-reactive protein levels. Secondary mechanistic measures were cardiovascular variability indexes of autonomic nervous system function, pubertal development, and serum levels of cortisol, leptin, and sex hormones. RESULTS: The MS was completely absent in adolescents with low IAF and was present in 13.8% of males and 8.3% of females with high IAF. Excess IAF was associated with a higher homeostasis model assessment index (0.5 [95% confidence interval (CI), 0.3 to 0.8]; P < .001) and triglycerides level (17.7 mg/dL [to convert to millimoles per liter, multiply by 0.0113] [95% CI, 9.7 to 25.7 mg/dL]; P < .001), lower high-density lipoprotein cholesterol level (-3.9 mg/dL [to convert to millimoles per liter, multiply by 0.0259] [95% CI, -6.2 to -1.5 mg/dL]; P = .003), and higher C-reactive protein level (0.03 mg/L [to convert to nanomoles per liter, multiply by 9.524] [95% CI, 0.01 to 0.05 mg/L]; P = .003). High IAF was associated with elevations of BP and sympathetic activity in males only (higher systolic BP, 6 mm Hg [95% CI, 1 to 11 mm Hg]; P = .02 and low-frequency power of diastolic BP, 629 mm Hg2 [95% CI, 37 to 1222 mm Hg2]; P = .04). CONCLUSIONS: Our results suggest that, already in adolescence, accumulation of IAF may promote development of the MS, affecting the metabolic and inflammatory components similarly in both sexes but influencing BP adversely only in males. The latter may be attributed, in part, to the augmentation of sympathetic activity also seen only in males.