Multitrait genome association analysis identifies new susceptibility genes for human anthropometric variation in the GCAT cohort.

BACKGROUND: Heritability estimates have revealed an important contribution of SNP variants for most common traits; however, SNP analysis by single-trait genome-wide association studies (GWAS) has failed to uncover their impact. In this study, we applied a multitrait GWAS approach to discover additional factor of the missing heritability of human anthropometric variation. METHODS: We analysed 205 traits, including diseases identified at baseline in the GCAT cohort (Genomes For Life- Cohort study of the Genomes of Catalonia) (n=4988), a Mediterranean adult population-based cohort study from the south of Europe. We estimated SNP heritability contribution and single-trait GWAS for all traits from 15 million SNP variants. Then, we applied a multitrait-related approach to study genome-wide association to anthropometric measures in a two-stage meta-analysis with the UK Biobank cohort (n=336 107). RESULTS: Heritability estimates (eg, skin colour, alcohol consumption, smoking habit, body mass index, educational level or height) revealed an important contribution of SNP variants, ranging from 18% to 77%. Single-trait analysis identified 1785 SNPs with genome-wide significance threshold. From these, several previously reported single-trait hits were confirmed in our sample with LINC01432 (p=1.9×10-9) variants associated with male baldness, LDLR variants with hyperlipidaemia (ICD-9:272) (p=9.4×10-10) and variants in IRF4 (p=2.8×10-57), SLC45A2 (p=2.2×10-130), HERC2 (p=2.8×10-176), OCA2 (p=2.4×10-121) and MC1R (p=7.7×10-22) associated with hair, eye and skin colour, freckling, tanning capacity and sun burning sensitivity and the Fitzpatrick phototype score, all highly correlated cross-phenotypes. Multitrait meta-analysis of anthropometric variation validated 27 loci in a two-stage meta-analysis with a large British ancestry cohort, six of which are newly reported here (p value threshold <5×10-9) at ZRANB2-AS2, PIK3R1, EPHA7, MAD1L1, CACUL1 and MAP3K9. CONCLUSION: Considering multiple-related genetic phenotypes improve associated genome signal detection. These results indicate the potential value of data-driven multivariate phenotyping for genetic studies in large population-based cohorts to contribute to knowledge of complex traits.

Decreased lipid metabolism but increased FA biosynthesis are coupled with changes in liver microRNAs in obese subjects with NAFLD.

BACKGROUND/OBJECTIVE: Many controversies regarding the association of liver miRNAs with obesity and nonalcoholic fatty liver diseases (NAFLD) call for additional validations. This study sought to investigate variations in genes and hepatic miRNAs in a sample of obese patients with or without NAFLD and human hepatocytes (HH). SUBJECTS/METHODS: A total of 60 non-consecutive obese women following bariatric surgery were recruited. Subjects were classified as NAFLD (n=17), borderline (n=24) and controls (n=19) with normal enzymatic profile, liver histology and ultrasound assessments. Profiling of 744 miRNAs was performed in 8 obese women with no sign of hepatic disease and 11 NAFLD patients. Additional validation and expression of genes related to de novo fatty acid (FA) biosynthesis, uptake, transport and ß-oxidation; glucose metabolism, and inflammation was tested in the extended sample. Induction of NAFLD-related genes and miRNAs was examined in HepG2 cells and primary HH treated with palmitic acid (PA), a combination of palmitate and oleic acid, or high glucose, and insulin (HG) mimicking insulin resistance in NAFLD. RESULTS: In the discovery sample, 14 miRNAs were associated with NAFLD. Analyses in the extended sample confirmed decreased miR-139-5p, miR-30b-5p, miR-122-5p and miR-422a, and increased miR-146b-5p in obese subjects with NAFLD. Multiple linear regression analyses disclosed that NAFLD contributed independently to explain miR-139-5p (P=0.005), miR-30b-5p (P=0.005), miR-122-5p (P=0.021), miR-422a (P=0.007) and miR-146a (P=0.033) expression variance after controlling for confounders. Decreased miR-122-5p in liver was associated with impaired FA usage. Expression of inflammatory and macrophage-related genes was opposite to decreased miR-30b-5p, miR-139-5p and miR-422a, whereas increased miR-146b-5p was associated with FABP4 and decreased glucose metabolism and FA mobilization. In partial agreement, PA (but not HG) led to decreased miR-139-5p, miR-30b-5p, miR-422a and miR-146a in vitro, in parallel with increased lipogenesis and FA transport, decreased glucose metabolism and diminished FA oxidation. CONCLUSION: This study confirms decreased liver glucose and lipid metabolism but increased FA biosynthesis coupled with changes in five unique miRNAs in obese patients with NAFLD.

Thyroid hormone receptor alpha gene variants increase the risk of developing obesity and show gene-diet interactions.

OBJECTIVE: Thyroid hormone receptor-beta resistance has been associated with metabolic traits. THRA gene sequencing of an obese woman (index case) who presented as empirical thyroid hormone receptor-α (THRA) resistance, disclosed a polymorphism (rs12939700) in a critical region involved in TRα alternative processing. DESIGN AND SUBJECTS: THRA gene variants were evaluated in three independent europid populations (i) in two population cohorts at baseline (n=3417 and n=2265), 6 years later (n=2139) and (ii) in 4734 high cardiovascular risk subjects (HCVR, PREDIMED trial). RESULTS: The minor allele of the index case polymorphism (rs12939700), despite having a very low frequency (4%), was significantly associated with higher body mass index (BMI) (P=0.042) in HCVR subjects. A more frequent THRA polymorphism (rs1568400) was associated with higher BMI in subjects from the population (P=0.00008 and P=0.05) after adjusting for several confounders. Rs1568400 was also strongly associated with fasting triglycerides (P dominant=3.99 × 10(-5)). In the same sample, 6 years later, age and sex-adjusted risk of developing obesity was significantly increased in GG homozygotes (odds ratio 2.93 (95% confidence interval, 1.05-6.95)). In contrast, no association between rs1568400 and BMI was observed in HCVR subjects, in whom obesity was highly prevalent. This might be explained by the presence of an interaction (P <0.001) among the rs1568400 variant, BMI and saturated fat intake. Only when saturated fat intake was high (>24.5 g d(-1)), GG carriers showed a significantly higher BMI than A carriers after controlling for energy intake and physical activity. CONCLUSIONS: THRA gene polymorphisms are associated with obesity development. This is a novel observation linking the THRA locus to metabolic phenotypes.

Correlation of BDNF blood levels with interoceptive awareness and maturity fears in anorexia and bulimia nervosa patients.

Association studies and rodent models suggest a major role for BDNF (brain-derived neurotrophic factor) in feeding regulation. Altered BDNF blood levels have been associated with eating disorders (ED) and their related psychopathological traits. Since the influence of BDNF on self-reported eating disorder inventory scores (EDI) has not been tested, we investigated the correlation of EDI scales with BDNF plasma levels. BDNF levels were measured by (ELISA), and the EDI questionnaire was administered in a total of 81 ED patients. The relationship between BDNF levels and EDI scores was calculated using a general linear model. After correcting for multiple testing, BDNF plasma levels negatively correlated with the EDI total score (R (2) = 0.26; p = 4.09 x 10(-4)), interoceptive awareness (R (2) = 0.26; p = 1.96 x 10(-4)), and maturity fears (R (2) = 0.13; p = 6.92 x 10(-4)). When subdividing according to the main diagnoses, interoceptive awareness presented significant correlations with BDNF blood levels in both the anorexia nervosa (R (2) = 0.33, p = 0.0026) and bulimia nervosa groups (R (2) = 0.10; p = 0.008). Our data suggest that BDNF levels may influence the severity of the ED by modulating the associated psychopathology, in particular through the impairment of interoceptive awareness.

Altered brain-derived neurotrophic factor blood levels and gene variability are associated with anorexia and bulimia.

Murine models and association studies in eating disorder (ED) patients have shown a role for the brain-derived neurotrophic factor (BDNF) in eating behavior. Some studies have shown association of BDNF -270C/T single-nucleotide polymorphism (SNP) with bulimia nervosa (BN), while BDNF Val66Met variant has been shown to be associated with both BN and anorexia nervosa (AN). To further test the role of this neurotrophin in humans, we screened 36 SNPs in the BDNF gene and tested for their association with ED and plasma BDNF levels as a quantitative trait. We performed a family-based association study in 106 ED nuclear families and analyzed BDNF blood levels in 110 ED patients and in 50 sib pairs discordant for ED. The rs7124442T/rs11030102C/rs11030119G haplotype was found associated with high BDNF levels (mean BDNF TCG haplotype carriers = 43.6 ng/ml vs. mean others 23.0 ng/ml, P = 0.016) and BN (Z = 2.64; P recessive = 0.008), and the rs7934165A/270T haplotype was associated with AN (Z =-2.64; P additive = 0.008). The comparison of BDNF levels in 50 ED discordant sib pairs showed elevated plasma BDNF levels for the ED group (mean controls = 41.0 vs. mean ED = 52.7; P = 0.004). Our data strongly suggest that altered BDNF levels modulated by BDNF gene variability are associated with the susceptibility to ED, providing physiological evidence that BDNF plays a role in the development of AN and BN, and strongly arguing for its involvement in eating behavior and body weight regulation.

Increased cerebral activity in Parkinson's disease patients carrying the DRD2 TaqIA A1 allele during a demanding motor task: a compensatory mechanism?

Previous studies suggest that neuroimaging techniques are useful for detecting the effects of functional genetic polymorphisms on brain function in healthy subjects or in patients presenting with psychiatric or neurodegenerative conditions. Former evidence showed that individuals carrying risk alleles displayed broader patterns of brain activity during behavioural and cognitive tasks, despite being clinically comparable to non-carriers. This suggests the presence of compensatory brain mechanisms. In the present study, we investigated this effect in Parkinson's disease (PD) patients carrying the DRD2 TaqIA A1 allelic variant. This variant may confer an increased risk of developing the disease and/or influence the clinical presentation. During a complex sequential motor task, we evidenced by functional magnetic resonance imaging that A1 allele carriers activated a larger network of bilateral cerebral areas than non-carriers, including cerebellar and premotor regions. Both groups had similar clinical and demographic measures. In addition, their motor performance during the functional magnetic resonance experiment was comparable. Therefore, our conclusions, pending replication in a larger sample, seem to reflect the recruitment of compensatory cerebral resources during motor processing in PD patients carrying the A1 allele.

Abnormal orbitofrontal development due to prematurity.

OBJECTIVE: To investigate the effects of prematurity on sulcal formation. METHODS: We evaluated the depth and volume of the primary olfactory sulcus (developed at 16 weeks' gestation) and the secondary orbital sulci (which start to develop at 28 weeks' gestation) in a sample of 22 adolescents with history of very-preterm birth (VPTB). We compared this preterm sample with a sample of subjects born at term and matched by age, gender, and sociocultural status. The Anatomist/BrainVISA 3.0.1 package was used to identify and quantify the sulci. In addition, voxel-based morphometry (VBM) was used to analyze possible reductions of gray and white matter in the orbitofrontal area. RESULTS: Compared with controls, we found a significant reduction in the secondary sulci depth but not in the primary sulcus in the VPTB. VBM analysis showed reduced gray-matter volume in VPTB in the orbital region. CONCLUSIONS: Premature birth affects cerebral gyrification, and this impairment is not reversible during childhood. Identification of the specific factors involved in abnormal brain maturation may lead to effective interventions.

Cerebral correlates of declarative memory dysfunctions in early traumatic brain injury.

We investigated residual brain damage in subjects who suffered severe traumatic brain injury (TBI) in childhood, and its relationship with declarative memory impairment. Magnetic resonance imaging (MRI) volumetric data and memory performance were compared between 16 adolescents with antecedents of severe TBI and 16 matched normal controls. Volumes of grey matter, white matter, cerebrospinal fluid (CSF), hippocampus, and caudate nuclei were measured. Verbal memory was assessed by the Rey's Auditory Verbal Learning test and visual memory by the Rey's Complex Figure. TBI patients performed significantly worse than controls in both verbal and visual memory. Patients presented decreased white matter volume and increased CSF. The hippocampus was reduced, but not the caudate nuclei. Memory performance correlated with CSF. Plasticity is incomplete for structural and functional deficits in children with TBI. Hippocampal atrophy, white matter loss, and memory impairment remain until adolescence. Memory sequelae are related more to diffuse brain injury, as reflected by MRI findings of increased CSF, than to hippocampal injury.

Apolipoproteins E and C1 and brain morphology in memory impaired elders.

Previous research has shown that polymorphisms of the apolipoproteins E ( APOE) and APOC1 represent genetic risk factors for dementia and for cognitive impairment in the elderly. The brain mechanisms by which these genetic variations affect behavior or clinical severity are poorly understood. We studied the effect of APOE and APOC1 genes on magnetic resonance imaging measures in a sample of 50 subjects with age-associated memory impairment. The APOE E4 allele was associated with reduced left hippocampal volumes and APOE*E3 status was associated with greater frontal lobe white matter volumes. However, no APOE effects were observed when analyses accounted for other potential confounding variables. The effects of APOC1 on hippocampal volumes appeared to be more robust than those of the APOE polymorphism. However, no modulatory effects on brain morphology outside the medial temporal lobe region were observed when demographic variables, clinical status, and other anatomical brain measurements were taken into consideration. Our results suggest that the role of the APOC1 polymorphism in brain morphology of the cognitively impaired elderly should be examined in further studies.

(1)H-MR spectroscopy is sensitive to subtle effects of perinatal asphyxia.

The authors performed neuropsychological and (1)H-MRS studies in 18 subclinical patients with antecedents of perinatal asphyxia (PA) and in 18 matched control subjects. Patients with PA showed reduced values of N-acetylaspartate (NAA) in both the basal ganglia and the midtemporal region (MTR) and reduced NAA/choline values in the MTR. Neuropsychological testing showed group differences in tasks related to attention and memory. These results indicate persistent dysfunctions in cerebral structures vulnerable to hypoxia and demonstrate the utility of MRS for the long-term evaluation of cerebral sequelae of neonatal asphyxia.

[Study of the long term sequelae of traumatic brain injury: evaluation of declarative and procedural memory, and its neuroanatomic substrate]. / Estudio de las secuelas a largo plazo de los traumatismos craneoencefálicos: evaluación de la memoria declarativa y procedimental y de su sustrato neuroanatómico.

INTRODUCTION AND OBJECTIVES: The hippocampus and the striatum have been proposed as respectively cerebral substrates of declarative and procedural memory. Both structures are vulnerable to traumatic brain injury. Although declarative and procedural memory have been reported to be impaired in traumatic brain injury (TBI), volumetric measures have so far failed to associate this impairment with atrophy of hippocampal and striatal structures. In our study, we investigated the profile of declarative and procedural memory in children who suffered from moderate to severe traumatic brain injury during childhood (injury test interval: 9.42+/-1.98 years). PATIENTS AND METHODS: Nineteen patients and matched controls were evaluated on tests of declarative memory and motor learning. Results showed that TBI subjects exhibit poorer performance in both tasks. Moreover, structural magnetic resonance images were obtained from TBI subjects. In order to relate neuropsychological performance with hippocampal and neostriatal volumetric data, correlation analyses were performed. RESULTS: Significant positive correlations were obtained between hippocampal volume and memory for objects. Striatal volume correlated positively with motor learning and with verbal memory. CONCLUSIONS: It thus seems that plasticity does not completely compensate for the memory deficits resultant from neural loss in the immature brain.

Estudio de las secuelas a largo plazo de los traumatismos craneoencefálicos: evaluación de la memoria declarativay procedimental y de su sustrato neuroanatómico / Study of the long term sequelae of traumatic brain injury: evaluation of declarative and procedural memory, and its neuroanatomic substrate

Introducción y objectivos. Los estudios realizados hasta la actualidad permiten considerar el hipocampo y el estriado como el sustrato neural de las memorias declarativa y procedimental, respectivamente. Si bien ambas estructuras son vulnerables al traumatismo craneoencefálico, y diversos estudios han observado que tanto la memoria declarativa como la procedimental también decaen a consecuencia de traumatismo craneoencefálico, los estudios volumétricos realizados hasta ahora no muestran evidencia de la relación entre la atrofia de ambas estructuras y el grado de alteración de la memoria. El presente estudio se centra en investigar el grado de alteración de las memorias declarativa y procedimental en niños que, de pequeños, sufrieron traumatismo craneoencefálico de moderado a grave. Pacientes y métodos. Diecinueve pacientes y sus respectivos controles fueron evaluados en tareas de memoria declarativa y aprendizaje motor. Los resultados mostraron que los sujetos con traumatismo craneoencefálico exhibían un peor rendimiento en ambas tareas. Además, para relacionar el rendimiento neuropsicológico con los datos volumétricos del hipocampo y el estriado, se realizaron análisis de correlaciones. Resultados. Se encontraron correlaciones positivas entre el volumen del hipocampo y la memoria para objetos del test `objeto-localización'. Por su parte, el volumen del estriado correlacionaba positivamente con el aprendizaje motor y la memoria verbal. Conclusión. Los resultados obtenidos sugieren que los mecanismos de plasticidad no compensan completamente los déficit de memoria resultantes de la pérdida neural en el cerebro immaduro (AU)

MRI and genetic correlates of cognitive function in elders with memory impairment.

The present study investigated the relationship between genetic variation, MRI measurements and neuropsychological function in a sample of 58 elders exhibiting memory decline. In agreement with previous reports, we found that the epsilon4 allele of the apolipoprotein E (APOE) and the D allele of the angiotensin converting enzyme (ACE) polymorphisms negatively modulated the cognitive performance. Further, we found an association between the A allele of the apolipoprotein C1 (APOC1) polymorphism and poorer memory and frontal lobe function. No clear associations emerged between MRI measures of white matter lesions (WML) or hippocampal sulcal cavities (HSC) and the cognitive performance after controlling for age effects. Further, the degree of WML or HSC lesions was in general not predisposed genetically except for the presence of the A allele of the APOC1 polymorphism that was related to a higher severity of HSC scores. Our results suggest that WML or HSC do not represent important brain correlates of genetic influences on cognitive performance in memory impaired subjects.

Correlation of atrophy measures on MRI with neuropsychological sequelae in children and adolescents with traumatic brain injury.

To examine the relationship between neuropsychological sequelae and atrophy parameters from magnetic resonance imaging (MRI) following paediatric moderate-to-severe traumatic brain injury (TBI), 19 head injured children and adolescents were studied at least 6 years after injury. Three-dimensional MRI scans were obtained. A semi-automatic computerized method was used to estimate ventricular volumes and the corpus callosum area. Tests of intellectual, memory, visuospatial, frontal lobe, and motor speed functioning were administered to all patients and to 19 matched normal control subjects. Patients' performance significantly differed from controls in general intellectual function, visual memory, visuospatial and frontal lobe tests. The corpus callosum area correlated strongly with several measures involving processing speed and visuospatial function. Ventricular enlargement was less related to neuropsychological outcome. In conclusion, quantitative measurement of the corpus callosum on MRI reflects neuropsychological outcome better than ventricular dilation in paediatric patients.

MRI atrophy parameters related to cognitive and motor impairment in Parkinson's disease.

BACKGROUND: Patients with Parkinson's disease (PD) show specific neuropsychological deficits in attention, memory, visuospatial or frontal lobe functions, which can arise from degeneration of different cerebral structures. OBJECTIVE: The aim of the present study was to analyze the role of focal degeneration (basal ganglia and substantia nigra) and diffuse cerebral atrophy (ventricular enlargement) in motor/cognitive impairment in PD. PATIENTS AND METHODS: We administered to 14 patients with advanced PD the following tests: Purdue Pegboard, Rey's Auditory-Verbal Learning test (RAVLT), Benton's Line Orientation, Trail Making, phonemic verbal fluency and Stroop test. Ventricular system, caudate and putamen nuclei and pars compacta of the substantia nigra were quantitatively measured by magnetic resonance imaging. Correlation analyses were carried out. RESULTS: The results showed that ventricular enlargement is negatively correlated with the performance on RAVLT and Stroop test. No relationship was found between caudate atrophy and cognitive deficits. Degeneration of putamen nucleus was found to be associated with motor deficits. CONCLUSION: Memory and frontal impairment are related to diffuse cerebral degeneration and the motor deficit is related to degeneration of the putamen nucleus.

Parámetros de atrofia por IRM relacionados con alteraciones cognitivas y motoras en la enfermedad de Parkinson / MRI atrophy parameters related to cognitive and motor impairment in Parkinson's disease

FUNDAMENTO: Los pacientes con la enfermedad de Parkinson (EP) manifiestan déficit neuropsicológicos en atención, memoria, visuospaciales o frontales, los cuales pueden ser debidos a la degeneración de diferentes estructuras cerebrales. OBJETIVO: El objetivo del presente estudio consistió en analizar el papel de la degeneración focal (ganglios basales y sustancia negra) y la atrofia cerebral difusa (dilatación ventricular) en la alteración motora/cognitiva en la EP. PACIENTES Y MÉTODOS: Se administraron a 14 pacientes con EP avanzada las siguientes pruebas: Purdue Pegboard, Prueba de Aprendizaje AuditivoVerbal de Rey (RAVLT), Orientación de Líneas de Benton, Trail Making, fluencia verbal fonética y test de Stroop. Se midieron cuantitativamente, a partir de imágenes de resonancia magnética, el sistema ventricular, núcleo caudado, putamen y la parte compacta de la sustancia negra. Se realizaron análisis de correlación. RESULTADOS: Los resultados demostraron que la dilatación ventricular está negativamente correlacionada con el rendimiento en el RAVLT y en el test de Stroop.No se encontró correlación entre la atrofia del caudado y los déficit cognitivos. Se halló relación entre la degeneración del núcleo putamen y los déficit motores. CONCLUSIóN: La alteración frontal y en memoria está relacionada con la degeneración cerebral difusa, en tanto que el déficit motor se relaciona con la degeneración del núcleo putamen (AU)

Neuroradiological and clinical findings in rhombencephalosynapsis.

Rhombencephalosynapsis is an unusual disorder characterised by maldevelopment of the rhombencephalon, sometimes with supratentorial midline anomalies. We report MRI findings in a 39-year-old woman, the oldest in the literature. MRI demonstrated hypoplasia of the cerebellar vermis, with fusion of the cerebellar hemispheres and abnormally oriented folia. Supratentorial anomalies were also seen.

[Application of magnetic resonance spectroscopy in the study of brain disease]. / Aplicaciones de la espectroscopía por resonancia magnética en el estudio de la patología cerebral.

INTRODUCTION AND OBJECTIVE: Magnetic resonance spectroscopy (MRS) is a non-invasive technique used for the neurochemical study of the brain in vivo. The aim of this work is to review the main investigations that have focused on the study of cerebral pathology. DEVELOPMENT: Cerebral MRS studies started in 1983 but the maximum development has been in the 90's. The pathologies more investigated were Alzheimer's disease, multiple sclerosis, schizophrenia, and depression. Although several nuclei can be observed the most investigated are phosphor (P31) and hydrogen (H1). Nowadays proton MRS is the more frequently used technique. The low levels of N-acetyl-aspartate are a good indicator of neuronal loss. Their determination is complementary to the volumetric structural studies from magnetic resonance imaging. The peak of myo-inositol seems to be a neurochemical marker for the Alzheimer's disease. CONCLUSIONS: MRS have contributed to the increase of knowledge about the physiopathology of normal aging, degenerative processes, demyelinating and psychiatric diseases. Potentially can contribute to differential diagnose in Alzheimer's and Parkinson's diseases. Recently it has also been opened a new research potential in the field of the pharmacological treatment effects in discrete cerebral regions.

Cortical laminar necrosis caused by immunosuppressive therapy and chemotherapy.

We report three patients in whom neurologic symptoms and cortical laminar necrosis developed after immunosuppressive treatment (cyclosporin A and FK 506) and polychemotherapy (vincristine and methotrexate). Initial neuroradiologic studies showed cortical and white matter involvement. Follow-up studies showed cortical hyper-intense lesions on T1-weighted MR images, consistent with cortical laminar necrosis. The clinical and radiologic data indicate that a transient hypoxic-ischemic process could have been responsible for the encephalic lesions in these three patients.