Common variants in FTO are not significantly associated with obesity-related phenotypes among Samoans of Polynesia

The association between obesity and the fat mass and obesity-associated (FTO) gene has been widely replicated among Caucasian populations. The limited number of studies assessing its significance in Asian populations has been somewhat conflicting. We performed a genetic association study of 51 tagging, genome-wide association studies, and imputed single nucleotide polymorphisms with 12 measures of adiposity and skeletal robustness in two Samoan populations of Polynesia. We included 465 and 624 unrelated American Samoan and Samoan individuals, respectively; these populations derive from a single genetic background traced to Southeast Asia and represent one sociocultural unit, although they are economically disparate with distinct environmental exposures. American Samoans were significantly larger than Samoans in all measures of obesity and most measures of skeletal robustness. In separate analyses of American Samoa and Samoa, we found a total of 36 nominal associations between FTO variants and skeletal and obesity measures. The preponderance of these nominal associations (32 of 36) was observed in the Samoan population, and predominantly with skeletal rather than fat mass measures (28 of 36). All significance disappeared, however, following corrections for multiple testing. Based on these findings, it could be surmised that FTO is not likely a major obesity locus in Polynesian populations.     

Genetic variation at the perilipin (PLIN) locus is associated with obesity-related phenotypes in White women

Perilipin coats intracellular lipid droplets and modulates adipocyte lipolysis. We have evaluated the association between several polymorphisms at the perilipin (PLIN) locus (PLIN1 : 6209T > C, PLIN4 : 11482G > A, PLIN5 : 13041A > G, and PLIN6 : 14995A > T) with obesity-related phenotypes in 1589 White subjects randomly selected from a general Spanish population. In women (n = 801), the less common alleles of PLIN1 and PLIN4, in strong linkage disequilibrium (D' : 0.96), were significantly associated with lower body mass index. Carriers of the allele 2 (6209C) at the PLIN1 locus weighed significantly less (-2.2 kg; p = 0.007) than women homozygotes for the wild-type genotype. The same was true for 11482A carriers at PLIN4 (p = 0.01). Moreover, the PLIN4 variant was associated with significantly lower waist-to-hip ratio, plasma glucose, and triacylglycerol concentrations. No significant associations with these obesity-related phenotypes were found in men. In agreement with these results, statistically significant gene-gender interactions were obtained when the risk of obesity was estimated (281 subjects were obese and 1308 non-obese). Only in women, PLIN1 and PLIN4 variant alleles (6209C and 11482A) were associated with a lower obesity risk [Odds ratio (OR) = 0.58, 95% confidence interval (CI): 0.38-0.93 and OR = 0.56, 95% CI: 0.36-0.89, respectively]. In summary, our data suggest that common alleles at the PLIN locus modulate body weight and metabolic variables in humans.     

Association analyses of the INSIG2 polymorphism in the obesity and cholesterol levels of Korean populations

Background  

While INSIG2 has been reported to be associated with BMI in many populations, conflicting results have prevented consensus over its role. In analyses of mice and cell cultures the gene has been found to be involved in the regulation of cholesterol synthesis; however, no relationship has been found with cholesterol metabolism in human epidemiological research. Therefore, this study attempts to assess the effect of rs7566605 near INSIG2 on both obesity- and cholesterol-related traits in Koreans.     

TP53 R72P and MDM2 SNP309 polymorphisms in modification of childhood acute lymphoblastic leukemia susceptibility

Genomic and immunologic surveillance mechanisms are crucial in protection from cancer. The tumor suppressor protein p53, encoded by TP53, is a major regulator of genome surveillance. Among the natural sequence variants of TP53, rs1042522 (R72P) modifies the risk for solid tumors. To investigate its relevance in childhood acute lymphoblastic leukemia (ALL) susceptibility, we genotyped 114 cases and 414 newborn controls from Wales (UK) for polymorphisms in TP53 (R72P), its negative regulator MDM2 (single-nucleotide polymorphism SNP309, rs2279744), and selected HLA complex genes whose products interact with TP53. TP53 R72P showed a risk association with gene dosage effect (P=0.002) resulting in a strong association of homozygous genotype (OR=2.9, 95% CI=1.5–5.6) and no sex effect. SNP309 did not show any association with primary susceptibility to childhood ALL, even after stratification by sex. However, females with SNP309 minor allele had earlier onset of childhood ALL (median age at diagnosis was 36 months in females, but 60 months in males; P=0.002). The HLA complex genes did not show any statistically significant interaction with R72P. We have therefore identified TP53 R72P as a possible risk modifier for childhood ALL and the association of MDM2 with age at onset with sex effect suggests prenatal hormonal programming of childhood ALL susceptibility.     

A functional polymorphism in the SPINK5 gene is associated with asthma in a Chinese Han Population

Background  

Mutation in SPINK5 causes Netherton syndrome, a rare recessive skin disease that is accompanied by severe atopic manifestations including atopic dermatitis, allergic rhinitis, asthma, high serum IgE and hypereosinophilia. Recently, single nucleotide polymorphism (SNP) of the SPINK5 was shown to be significantly associated with atopy, atopic dermatitis, asthma, and total serum IgE. In order to determine the role of the SPINK5 in the development of asthma, a case-control study including 669 asthma patients and 711 healthy controls in Han Chinese was conducted.     

Analysis of common PTPN1 gene variants in type 2 diabetes, obesity and associated phenotypes in the French population

Background  

The protein tyrosine phosphatase-1B, a negative regulator for insulin and leptin signalling, potentially modulates glucose and energy homeostasis. PTP1B is encoded by the PTPN1 gene located on chromosome 20q13 showing linkage with type 2 diabetes (T2D) in several populations. PTPN1 gene variants have been inconsistently associated with T2D, and the aim of our study was to investigate the effect of PTPN1 genetic variations on the risk of T2D, obesity and on the variability of metabolic phenotypes in the French population.     

C4B null alleles are not associated with genetic polymorphisms in the adjacent gene CYP21A2 in autism

Background  

Research indicates that the etiology of autism has a strong genetic component, yet so far the search for genes that contribute to the disorder, including several whole genome scans, has led to few consistent findings. However, three studies indicate that the complement C4B gene null allele (i.e. the missing or nonfunctional C4B gene) is significantly more frequent in individuals with autism. Due to the close proximity of the CYP21A2 gene to the C4B locus (3 kb) it was decided to examine samples from autistic subjects, including many with known C4B null alleles for common CYP21A2 mutations.     

A novel c.-22T>C mutation in GALK1 promoter is associated with elevated galactokinase phenotype

Background  

Many genetic variations of GALK1 have been identified in the patients with galactokinase (GALK1) deficiency. However, the molecular characteristics of GALK1 in individuals with elevated GALK1 activity are relatively unknown.     

The INSIG2 rs7566605 genetic variant does not play a major role in obesity in a sample of 24,722 individuals from four cohorts

Background  

In a genome-wide association study performed in the Framingham Offspring Cohort, individuals homozygous for the rs7566605 C allele located upstream of insulin-induced gene 2 (INSIG2) were reported to incur an increased risk of obesity. This finding was later replicated in four out of five populations examined. The goal of the study reported here was to assess the role of the INSIG2 single nucleotide polymorphism (SNP) in susceptibility to obesity in the prospective longitudinal Atherosclerosis Risk in Communities (ARIC) study (n = 14,566) and in three other cohorts: the Coronary Artery Risk Development in Young Adults (CARDIA) study (n = 3,888), the Genetic Epidemiology Network of Arteriopathy (GENOA) study (n = 4,766), and extremely obese and lean individuals ascertained at the University of Ottawa (n = 1,502). The combined study sample is comprised of 24,722 white, African-American, and Mexican-American participants.     

The rs2030324 SNP of brain-derived neurotrophic factor (BDNF) is associated with visual cognitive processing in multiple sclerosis

Purpose: To investigate the associations between the rs2030324 SNP of brain-derived neurotrophic factor (BDNF) and neuropsychological (NP) test measures in multiple sclerosis (MS) patients. Background: BDNF regulates the survival of neuronal and non-neuronal cells and plays a critical role in neurochemical processes underlying learning and memory. Methods: A total of 209 MS patients (161 females; 48 males) underwent brain MRI and genotyping for BDNF rs2030324. The NP testing (n = 108) assessed processing speed, working memory, new learning and executive control. The MRI measurements included T1 and T2 lesion volume, whole brain, white and gray matter volumes, magnetization transfer imaging and regional subcortical brain volumes. Results: The T/T rs2030324 genotype group performed poorly on the Brief Visuospatial Memory Test-Revised (p = 0.031) and the Symbol Digit Modalities Test (p = 0.045) compared to the C/C genotype group. Because these NP tests both involve visual processing, the relationship with the volume of the thalamus was assessed. The BDNF rs2030324 genotype was associated with the volume of the left thalamus (p = 0.036). There were no significant associations with whole brain lesional and atrophy MRI measures. Conclusions: The C allele of BDNF rs2030324 is associated with protection against visual cognitive processing deficits via mechanisms that appear associated with the volume of the thalamus.     

A common SNP of MCPH1 is associated with cranial volume variation in Chinese population

Microcephaly (MCPH) genes are informative in understanding thegenetics and evolution of human brain volume. MCPH1 and abnormalspindle-like MCPH associated (ASPM) are the two known MCPH causinggenes that were suggested undergone recent positive selectionin human populations. However, previous studies focusing onlyon the two tag single nucleotide polymorphisms(SNPs) of MCPH1and ASPM failed to detect any correlation between gene polymorphismsand variations of brain volume and cognitive abilities. We conductedan association study on eight common SNPs of MCPH1 and ASPMin a Chinese population of 867 unrelated individuals. We demonstratethat a non-synonymous SNP (rs1057090, V761A in BRCA1 C-terminus(BRCT) domain) of MCPH1 other than the two known tag SNPs issignificantly associated with cranial volume in Chinese males.The haplotype analysis confirmed the association of rs1057090with cranial volume, and the homozygote males containing thederived alleles of rs1057090 have larger cranial volumes comparedwith those containing the ancestral alleles. No recent selectionsignal can be detected on this SNP, suggesting that the brainvolume variation in human populations is likely neutral or undervery weak selection in recent human history.     

Type 2 diabetes gene TCF7L2 polymorphism is not associated with fetal and postnatal growth in two birth cohort studies

Background  

An inverse association between birth weight and the risk of developing type 2 diabetes (T2D) in adulthood has been reported. This association may be explained by common genetic variants related to insulin secretion and resistance, since insulin is the most important growth factor in fetal life. The objective of this study was to examine whether T2D gene polymorphism TCF7L2 rs7903146 is associated with growth patterns from fetal life until infancy.     

TREM2 is associated with the risk of Alzheimer's disease in Spanish population

Two recent studies have reported the association of rs75932628-T in the TREM2 gene with the risk for Alzheimer's disease (AD). Rs75932628-T is a rare nonsynonymous variant (p.R47H) that confers a high risk of AD with an effect size similar to that of the APOE ?4 allele. However, this association has not been replicated in any independent studies to date. The allelic frequency of rs75932628 varies according to the population from 0.02% to 0.63% among healthy controls. In an attempt to replicate the association between rs75932628-T and AD risk, we genotyped rs75932628 in a cohort of 504 AD subjects and 550 healthy controls from a Spanish population. Rs75932628-T showed a minor allele frequency of 0.3% among this cohort. Interestingly, in our study, rs75932628-T was found exclusively in 1.4% of AD cases (7/504), including 4 early-onset AD cases, and in none of the controls (n = 0/550). Here, we report the first positive replication study in a Spanish population and confirm that TREM2 rs75932628-T is associated with the risk for AD.     

RIT2 variant is not associated with Parkinson's disease in a Taiwanese population

Recent genome-wide association studies of Parkinson's disease (PD) have identified the rs12456492 variant of the novel susceptibility loci, RIT2, as being associated with disease risk in a large white population. Studies among Asians are scarce. We genotyped RIT2 rs12456492 variant in a total of 1000 participants, comprising 500 patients with PD and 500 control subjects in a Taiwanese population. The frequency of GA/AA genotype was slightly higher in PD patients compared with controls, but was without statistical significance (odds ratio = 1.03, 95% confidence interval = 0.73–1.46, p = 0.86). We failed to replicate the RIT2 rs12456492 variant as a genetic risk factor for PD in our population.     

Search for the sex-determining switch in monotremes: Mapping WT1 , SF1 , LHX1 , LHX2 , FGF9 , WNT4 , RSPO1 and GATA4 in platypus

The duck-billed platypus has five pairs of sex chromosomes, but there is no information about the primary sex-determining switch in this species. As there is no apparent SRY orthologue in platypus, another gene must acquire the function of a key regulator of the gonadal male or female fate. SOX9 was ruled out from being this key regulator as it maps to an autosome in platypus. To check whether other genes in mammalian gonadogenesis could be the primary switch in monotremes, we have mapped a number of candidates in platypus. We report here the autosomal location of WT1, SF1, LHX1, LHX9, FGF9, WNT4 and RSPO1 in platypus, thus excluding these from being key regulators of sex determination in this species. We found that GATA4 maps to sex chromosomes Y₁ and X₂; however, it lies in the pairing region shown by chromosome painting to be homologous, so is unlikely to be either male-specific or differentially dosed in male and female.