Genetic variation in SH3-domain GRB2-like (endophilin)-interacting protein 1 has a major impact on fat mass

Objective:

The SH3-domain GRB2-like (endophilin)-interacting protein 1 (SGIP1) gene has been shown to be differentially expressed in the hypothalamus of lean versus obese Israeli sand rats (Psammomys obesus), and is suspected of having a role in regulating food intake. The purpose of this study was to assess the role of genetic variation in SGIP1 in human disease.
Subjects:

We performed single-nucleotide polymorphism (SNP) genotyping in a large family pedigree cohort from the island of Mauritius. The Mauritius Family Study (MFS) consists of 400 individuals from 24 Indo-Mauritian families recruited from the genetically homogeneous population of Mauritius. We measured markers of the metabolic syndrome, including diabetes and obesity-related phenotypes such as fasting plasma glucose, waist:hip ratio, body mass index and fat mass.
Results:

Statistical genetic analysis revealed associations between SGIP1 polymorphisms and fat mass (in kilograms) as measured by bioimpedance. SNP genotyping identified associations between several genetic variants and fat mass, with the strongest association for rs2146905 (P=4.7 × 10−5). A strong allelic effect was noted for several SNPs where fat mass was reduced by up to 9.4% for individuals homozygous for the minor allele.
Conclusions:

Our results show association between genetic variants in SGIP1 and fat mass. We provide evidence that variation in SGIP1 is a potentially important determinant of obesity-related traits in humans.

Bone marrow chimeric mice reveal a role for CX3CR1 in maintenance of the monocyte-derived cell population in the olfactory neuroepithelium

Macrophages in the olfactory neuroepithelium are thought to play major roles in tissue homeostasis and repair. However, little information is available at present about possible heterogeneity of these monocyte-derived cells, their turnover rates, and the role of chemokine receptors in this process. To start addressing these issues, this study used Cx3cr1gfp mice, in which the gene sequence for eGFP was knocked into the CX3CR1 gene locus in the mutant allele. Using neuroepithelial whole-mounts from Cx3cr1gfp/+ mice, we show that eGFP+ cells of monocytic origin are distributed in a loose network throughout this tissue and can be subdivided further into two immunophenotypically distinct subsets based on MHC-II glycoprotein expression. BM chimeric mice were created using Cx3cr1gfp/+ donors to investigate turnover of macrophages (and other monocyte-derived cells) in the olfactory neuroepithelium. Our data indicate that the monocyte-derived cell population in the olfactory neuroepithelium is actively replenished by circulating monocytes and under the experimental conditions, completely turned over within 6 months. Transplantation of Cx3cr1gfp/gfp (i.e., CX3CR1-deficient) BM partially impaired the replenishment process and resulted in an overall decline of the total monocyte-derived cell number in the olfactory epithelium. Interestingly, replenishment of the CD68lowMHC-II+ subset appeared minimally affected by CX3CR1 deficiency. Taken together, the established baseline data about heterogeneity of monocyte-derived cells, their replenishment rates, and the role of CX3CR1 provide a solid basis to further examine the importance of different monocyte subsets for neuroregeneration at this unique frontier with the external environment.

Ocean currents influence the genetic structure of an intertidal mollusc in southeastern Australia – implications for predicting the movement of passive dispersers across a marine biogeographic barrier

Major disjunctions among marine communities in southeastern Australia have been well documented, although explanations for biogeographic structuring remain uncertain. Converging ocean currents, environmental gradients, and habitat discontinuities have been hypothesized as likely drivers of structuring in many species, although the extent to which species are affected appears largely dependent on specific life histories and ecologies. Understanding these relationships is critical to the management of native and invasive species, and the preservation of evolutionary processes that shape biodiversity in this region. In this study we test the direct influence of ocean currents on the genetic structure of a passive disperser across a major biogeographic barrier. Donax deltoides (Veneroida: Donacidae) is an intertidal, soft-sediment mollusc and an ideal surrogate for testing this relationship, given its lack of habitat constraints in this region, and its immense dispersal potential driven by year-long spawning and long-lived planktonic larvae. We assessed allele frequencies at 10 polymorphic microsatellite loci across 11 sample locations spanning the barrier region and identified genetic structure consistent with the major ocean currents of southeastern Australia. Analysis of mitochondrial DNA sequence data indicated no evidence of genetic structuring, but signatures of a species range expansion corresponding with historical inundations of the Bassian Isthmus. Our results indicate that ocean currents are likely to be the most influential factor affecting the genetic structure of D. deltoides and a likely physical barrier for passive dispersing marine fauna generally in southeastern Australia.

Polyalanine repeat polymorphism in RUNX2 is associated with site-specific fracture in post-menopausal femals

Runt related transcription factor 2 (RUNX2) is a key regulator of osteoblast differentiation. Several variations within the RUNX2 gene have been found to be associated with significant changes in BMD, which is a major risk factor for fracture. In this study we report that an 18 bp deletion within the polyalanine tract (17A>11A) of RUNX2 is significantly associated with fracture. Carriers of the 11A allele were found to be nearly twice as likely to have sustained fracture. Within the fracture category, there was a significant tendency of 11A carriers to present with fractures of distal radius and bones of intramembranous origin compared to bones of endochondral origin (p = 0.0001). In a population of random subjects, the 11A allele was associated with decreased levels of serum collagen cross links (CTx, p = 0.01), suggesting decreased bone turnover. The transactivation function of the 11A allele showed a minor quantitative decrease. Interestingly, we found no effect of the 11A allele on BMD at multiple skeletal sites. These findings suggest that the 11A allele is a biologically relevant polymorphism that influences serum CTx and confers enhanced fracture risk in a site-selective manner related to intramembranous bone ossification.

Environmental and genetic determinants of vitamin D insufficiency in 12-month-old infants

We aimed to investigate the relationship between genetic and environmental exposure and vitamin D status at age one, stratified by ethnicity. This study included 563 12-month-old infants in the HealthNuts population-based study. DNA from participants' blood samples was genotyped using Sequenom MassARRAY MALDI-TOF system on 28 single nucleotide polymorphisms (SNPs) in six genes. Using logistic regression, we examined associations between environmental exposure and SNPs in vitamin D pathway and filaggrin genes and vitamin D insufficiency (VDI). VDI, defined as serum 25-hydroxyvitamin D3(25(OH)D3) level ≤50 nmol/L, was measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Infants were stratified by ethnicity determined by parent's country of birth. Infants formula fed at 12 months were associated with reduced odds of VDI compared to infants with no current formula use at 12 months. This association differed by ethnicity (P;bsubesub;= 0.01). The odds ratio (OR) of VDI was 0.29 for Caucasian infants (95% CI, 0.18-0.47) and 0.04 for Asian infants (95% CI, 0.006-0.23). Maternal vitamin D supplementation during pregnancy and/or breastfeeding were associated with increased odds of infants being VDI (OR, 2.39; 95% CI, 1.11-5.18 and OR, 2.5; 95% CI, 1.20-5.24 respectively). Presence of a minor allele for any GC SNP (rs17467825, rs1155563, rs2282679, rs3755967, rs4588, rs7041) was associated with increased odds of VDI. Caucasian infants homozygous (AA) for rs4588 had an OR of 2.49 of being associated with VDI (95% CI, 1.19-5.18). In a country without routine infant vitamin D supplementation or food chain fortification, formula use is strongly associated with a reduced risk of VDI regardless of ethnicity. There was borderline significance for an association between filaggrin mutations and VDI. However, polymorphisms in vitamin D pathway related genes were associated with increased likelihood of being VDI in infancy. © 2014 Elsevier B.V. All rights reserved.

Environmental enrichment ameliorates a motor coordination deficit in a mouse model of Rett syndrome Mecp2 gene dosage effects and BDNF expression

Rett syndrome, commonly associated with mutations of the methyl CpG-binding protein 2 (MECP2) gene, is characterised by an apparently normal early postnatal development followed by deterioration of acquired cognitive and motor coordination skills in early childhood. To evaluate whether environmental factors may influence the disease outcome of Rett syndrome, we tested the effect of environmental enrichment from 4 weeks of age on the behavioural competence of mutant mice harboring a Mecp2 tm1Tam-null allele. Our findings show that enrichment improves motor coordination in heterozygous Mecp2 +/− females but not Mecp2 −/y males. Standard-housed Mecp2 +/− mice had an initial motor coordination deficit on the accelerating rotarod, which improved with training then deteriorated in subsequent weeks. Enrichment resulted in a significant reduction in this coordination deficit in Mecp2 +/− mice, returning the performance to wild-type levels. Brain-derived neurotrophic factor (BDNF) protein levels were 75 and 85% of wild-type controls in standard-housed and environmentally enriched Mecp2 +/− cerebellum, respectively. Mecp2 −/y mice showed identical deficits of cerebellar BDNF (67% of wild-type controls) irrespective of their housing environment. Our findings demonstrate a positive impact of environmental enrichment in a Rett syndrome model; this impact may be dependent on the existence of one functional copy of Mecp2.

Sturnus vulgaris, mitochondrial selection, MATLAB code and microsatellite data

Here we provide MATLAB code used to simulate drift and selection between and within individuals, which has been used to investigate mitochondrial haplotype frequency shifts in Sturnus vulgaris. Also provided is a microsatellite data set used to assess whether empirical allele frequency shifts were likely to be caused by admixture. These files support and upcoming publication, which concludes that within-individuals selection on mitochondrial DNA best explains empirical data.

Expected shannon entropy and shannon differentiation between subpopulations for neutral genes under the finite island model

Shannon entropy H and related measures are increasingly used in molecular ecology and population genetics because (1) unlike measures based on heterozygosity or allele number, these measures weigh alleles in proportion to their population fraction, thus capturing a previously-ignored aspect of allele frequency distributions that may be important in many applications; (2) these measures connect directly to the rich predictive mathematics of information theory; (3) Shannon entropy is completely additive and has an explicitly hierarchical nature; and (4) Shannon entropy-based differentiation measures obey strong monotonicity properties that heterozygosity-based measures lack. We derive simple new expressions for the expected values of the Shannon entropy of the equilibrium allele distribution at a neutral locus in a single isolated population under two models of mutation: the infinite allele model and the stepwise mutation model. Surprisingly, this complex stochastic system for each model has an entropy expressable as a simple combination of well-known mathematical functions. Moreover, entropy- and heterozygosity-based measures for each model are linked by simple relationships that are shown by simulations to be approximately valid even far from equilibrium. We also identify a bridge between the two models of mutation. We apply our approach to subdivided populations which follow the finite island model, obtaining the Shannon entropy of the equilibrium allele distributions of the subpopulations and of the total population. We also derive the expected mutual information and normalized mutual information ("Shannon differentiation") between subpopulations at equilibrium, and identify the model parameters that determine them. We apply our measures to data from the common starling (Sturnus vulgaris) in Australia. Our measures provide a test for neutrality that is robust to violations of equilibrium assumptions, as verified on real world data from starlings.

Linking the serotonin transporter gene, family environments, hippocampal volume and depression onset: a prospective imaging gene × environment analysis

A single imaging gene-environment (IGxE) framework that is able to simultaneously model genetic, neurobiological, and environmental influences on psychopathology outcomes is needed to improve understanding of how complex interrelationships between allelic variation, differences in neuroanatomy or neuroactivity, and environmental experience affect risk for psychiatric disorder. In a longitudinal study of adolescent development we demonstrate the utility of such an IGxE framework by testing whether variation in parental behavior at age 12 altered the strength of an imaging genetics pathway, involving an indirect association between allelic variation in the serotonin transporter gene to variation in hippocampal volume and consequent onset of major depressive disorder by age 18. Results were consistent with the presence of an indirect effect of the serotonin transporter S-allele on depression onset via smaller left and right hippocampal volumes that was significant only in family environments involving either higher levels of parental aggression or lower levels of positive parenting. The previously reported finding of S-allele carriers' increased risk of depression in adverse environments may, therefore, be partly because of the effects of these environments on a neurobiological pathway from the serotonin transporter gene to depression onset that proceeds through variation in hippocampal volume. 

Association between apolipoprotein E polymorphisms and age-related macular degeneration: a HuGE review and meta-analysis

A possible association between apolipoprotein E polymorphisms and age-related macular degeneration has been investigated numerous times, with conflicting results. A previous analysis pooling results from four studies (Schmidt et al., Ophthalmic Genet 2002;23:209-23) suggested an association, but those investigators did not document allele frequencies, the magnitude of the association, or the possible genetic mode of action. Thus, the authors searched MEDLINE from 1966 to December 2005 for any English-language studies reporting genetic associations. Data and study quality were assessed in duplicate. Pooling was performed while checking for heterogeneity and publication bias. Frequencies of the E2 and E4 alleles in Caucasians were approximately 8% and 15%, respectively. Allele- and genotype-based tests of association indicated a risk effect of up to 20% for E2 and a protective effect of up to 40% for E4. E2 appeared to act in a recessive mode and E4 in a dominant mode. There appears to be a differential effect of the E2 and E4 alleles on the risk of age-related macular degeneration, although the possibility of survivor bias needs to be ruled out more definitively.