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1.  Myostatin and Follistatin Polymorphisms Interact with Muscle Phenotypes and Ethnicity 
We examined associations among myostatin (MSTN) 2379 A > G and 163 G > A and follistatin (FST) −5003 A > T and −833 G > T single nucleotide polymorphisms (SNP) on the muscle size and the strength response to resistance training (RT).
Subjects (n = 645, age = 24.1 ± 0.2 yr, body mass index [BMI] = 24.2 ± 0.2 kg·m−2) self-disclosed themselves as Caucasian (78.9%), African American (3.6%), Asian (8.4%), Hispanic (5.0%), or Other (4.2%). They were genotyped for MSTN 2379 A > G (n = 645), MSTN 163 G > A (n = 639), FST −5003 A > T (n = 580), and FST −833 G > T (n = 603). We assessed dynamic (one repetition maximum [1RM]) and isometric (maximum voluntary contraction [MVC]) muscle strength and size (cross-sectional area [CSA]) of the elbow flexors before and after 12 wk of unilateral upper-arm RT. Repeated-measures ANCOVA tested associations among genetic variants and muscle phenotypes with age and BMI as covariates.
Baseline MVC was greater among African Americans who were carriers of the MSTN G2379 allele (AG/GG, n = 15) than the A2379A homozygotes (n = 8; 64.2 ± 6.8 vs 49.8 ± 8.7 kg). African Americans who were carriers of the FST T−5003 allele (n = 12) had greater baseline 1RM (11.9 ± 0.7 vs 8.8 ± 0.5 kg) and CSA (24.4 ± 1.3 vs 19.1 ± 1.2 cm2) than African Americans with the A-5003A genotype (n = 14; P < 0.05). No MSTN or FST genotype and muscle phenotype associations were found among the other ethnic groups (P ≥ 0.05).
MSTN 2379 A > G and FST −5003 A > T were associated with baseline muscle strength and size among African Americans only. These ethnic-specific associations are hypothesis generating and should be confirmed in a larger sample of African Americans.
PMCID: PMC4147954  PMID: 19346981
2.  Genome-Wide Association Study of Receptive Language Ability of 12-Year-Olds 
Researchers have previously shown that individual differences in measures of receptive language ability at age 12 are highly heritable. In the current study, the authors attempted to identify some of the genes responsible for the heritability of receptive language ability using a genome-wide association approach.
The authors administered 4 Internet-based measures of receptive language (vocabulary, semantics, syntax, and pragmatics) to a sample of 2,329 twelve-year-olds for whom DNA and genome-wide genotyping were available. Nearly 700,000 single-nucleotide polymorphisms (SNPs) and 1 million imputed SNPs were included in a genome-wide association analysis of receptive language composite scores.
No SNP associations met the demanding criterion of genome-wide significance that corrects for multiple testing across the genome (p < 5 × 10–8). The strongest SNP association did not replicate in an additional sample of 2,639 twelve-year-olds.
These results indicate that individual differences in receptive language ability in the general population do not reflect common genetic variants that account for more than 3% of the phenotypic variance. The search for genetic variants associated with language skill will require larger samples and additional methods to identify and functionally characterize the full spectrum of risk variants.
PMCID: PMC3974169  PMID: 24687471
receptive language; adolescents; genome-wide association study; genetics
3.  Vascular Remodeling in Response to 12 wk of Upper Arm Unilateral Resistance Training 
Participation in regular aerobic exercise has been shown to increase arterial size and that exercise-induced vascular remodeling may be regional rather than systemic. However, these issues have been minimally investigated concerning resistance training.
To determine whether 1) resistance training of the nondominant arm elicits an increase in diameter of the brachial artery and 2) unilateral training induces arterial remodeling in the contralateral arm.
Twenty-four previously untrained participants, consisting of 18 females (aged 22.3 ± 5.1 yr) and 6 males (aged 21.7 ± 1.8 yr), participated in unilateral strength training of the biceps and triceps for 12 wk using their nondominant arm. Isotonic (one-repetition maximum, 1RM) and isometric (ISO) strength of the biceps were assessed before and after training on both arms. Brachial artery diameter and biceps muscle cross-sectional area (CSA) of both arms were also measured before and after training using magnetic resonance imaging (MRI).
Brachial artery diameter increased 5.47% (P < 0.05) in the nondominant trained arm with no change observed in the dominant untrained arm. Biceps CSA increased 18.3% (P < 0.05) in the trained arm with no change (P > 0.05) in the untrained limb. Nondominant 1RM and ISO strength increased by 35.1% and 16.8%, respectively (P < 0.05 for both), although there were no significant changes (P > 0.05) in the contralateral arm. A modest correlation was found between the increases in CSA and in brachial artery diameter (r2 = 0.19, P = 0.039).
These results indicate that upper arm vascular remodeling, manifesting as increased brachial artery diameter, can result from resistance training and that these changes are localized to the trained limb and associated with increases in CSA.
PMCID: PMC4107658  PMID: 19812518
4.  Allometric scaling of isometric biceps strength in adult females and the effect of body mass index 
The purposes of this study were to (1) derive and test allometric scaling models of biceps isometric strength using body mass (BM) and muscle cross-sectional area (CSA) as the scaling variables, (2) assess the influence of body mass index (BMI) by separating the cohort by BMI (normal <25 kg/m2 vs. overweight/obese ≥25 kg/m2) and repeating step 1, and (3) assess the effect of BMI on isometric strength allometrically adjusted for differences in CSA by comparing scaled strength between normal weight versus overweight/obese women. The participants were 183 women (18–39 years old) who reported no strength training in the prior year. Isometric strength and CSA of the biceps were assessed on the non-dominant arm. The CSA allometric model met all statistical criteria and produced a scaling exponent of 0.44. The BM model did not meet these criteria until the entire cohort was separated by BMI. The scaling exponents for normal weight and overweight/obese women were 1.48 and 0.35, respectively. These data suggest that BMI exerted an influence on the relationship between BM and allometrically scaled isometric strength and may be explained by previous studies demonstrating greater contribution of fat mass (FM) versus fat-free mass (FFM) to BMI in overweight/obese women. As such, allometric scaling models of isometric strength, especially in populations that are heterogeneous with regard to body composition, must be carefully tested and examined across the range of BMI. Isometric strength relative to CSA was not significantly different between groups. However, allometrically scaled strength, using CSA as the criterion variable, was significantly greater in overweight/obese women compared to those of normal weight. These data suggest that isometric strength in women is not completely determined by CSA and other factors such as intramuscular fat and muscle fiber type may be confounding or contributing factors.
PMCID: PMC4107660  PMID: 18648848
Allometric scaling; Muscle strength; Muscle cross-sectional area; Body mass index
5.  Association of Age with Muscle Size and Strength Before and After Short-Term Resistance Training in Young Adults 
The purpose of this study was to assess the association of age with muscle mass and strength in a group of young adults before and after 12 weeks of progressive resistance training. Eight hundred twenty-six young males and females (age 24.34 ± 5.69 yr, range 18–39 yr) completed a strictly supervised 12-week unilateral resistance training program of the nondominant arm. Isometric (maximal voluntary contraction [MVC]) and dynamic strength (1 repetition maximum [1RM]) of the elbow flexors and cross-sectional area (CSA) of the biceps-brachii using magnetic resonance imaging (MRI) scans were measured before and after training. Pearson correlation coefficients were calculated for size and strength variables and age. In addition, the cohort was divided into groups according to decade of life and differences assessed by analysis of variance. Age correlated significantly and positively with all pretraining measures of muscle size and strength (CSA: r = 0.191, p < 0.001; MVC: r = 0.109, p = 0.002; 1RM: r = 0.109, p = 0.002). Age was not related to the training-induced changes in CSA or MVC but was negatively associated with the change in 1RM (r = −0.217, p < 0.001). The study indicates that age does have a significant positive relationship with muscle size and strength in untrained young adults. Although age was negatively associated with improvements in 1RM, the effect of age was small relative to the improvements induced through resistance training, thus suggesting age does not limit response to training in any practical way during early adulthood.
PMCID: PMC4103410  PMID: 19749605
magnetic resonance imaging; muscle cross-sectional area; isometric strength; isotonic strength; supervised resistance training
6.  Computational modeling and analysis of hippocampal-prefrontal information coding during a spatial decision-making task 
We introduce a computational model describing rat behavior and the interactions of neural populations processing spatial and mnemonic information during a maze-based, decision-making task. The model integrates sensory input and implements working memory to inform decisions at a choice point, reproducing rat behavioral data and predicting the occurrence of turn- and memory-dependent activity in neuronal networks subserving task performance. We tested these model predictions using a new software toolbox (Maze Query Language, MQL) to analyse activity of medial prefrontal cortical (mPFC) and dorsal hippocampal (dCA1) neurons recorded from six adult rats during task performance. The firing rates of dCA1 neurons discriminated context (i.e., the direction of the previous turn), whilst a subset of mPFC neurons was selective for current turn direction or context, with some conjunctively encoding both. mPFC turn-selective neurons displayed a ramping of activity on approach to the decision turn and turn-selectivity in mPFC was significantly reduced during error trials. These analyses complement data from neurophysiological recordings in non-human primates indicating that firing rates of cortical neurons correlate with integration of sensory evidence used to inform decision-making.
PMCID: PMC3939443  PMID: 24624066
hippocampus; prefrontal cortex; decision making; computational modeling; information coding
7.  Effect of HLA-Matching Recipients to Donor Noninherited Maternal Antigens on Outcomes after Mismatched Umbilical Cord Blood Transplantation for Hematologic Malignancy 
Transplantation-related mortality (TRM) is high after HLA-mismatched umbilical cord blood (UCB) transplantation (UCBT). In utero, exposure to noninherited maternal antigen (NIMA) is recognized by the fetus, which induces Tregulator cells to that haplotype. It is plausible that UCBTs in which recipients are matched to donor NIMAs may alleviate some of the excess mortality associated with this treatment. To explore this concept, we used marginal matched-pair Cox regression analysis to compare outcomes in 48 NIMA-matched UCBTs (ie, the NIMA of the donor UCB unit matched to the patient) and in 116 non–NIMA-matched UCBTs. All patients had a hematologic malignancy and received a single UCB unit. Cases and controls were matched on age, disease, disease status, transplantation-conditioning regimen, HLA match, and infused cell dose. TRM was lower after NIMA-matched UCBTs compared with NIMA-mismatched UCBTs (relative risk, 0.48; P=.05; 18% versus 32% at 5 years posttransplantation). Consequently, overall survival was higher after NIMA-matched UCBT. The 5-year probability of overall survival was 55% after NIMA-matched UCBTs versus 38% after NIMA-mismatched UCBTs (P=.04). When faced with the choice of multiple HLA-mismatched UCB units containing adequate cell doses, selecting an NIMA-matched UCB unit may improve survival after mismatched UCBT.
PMCID: PMC3826155  PMID: 22814031
Permissive match; Regulatory T cells; Fetal immune response
8.  Leptin and Leptin Receptor Genetic Variants Associate with Habitual Physical Activity and the Arm Body Composition Response to Resistance Training 
Gene  2012;510(1):66-70.
We investigated the influence of Leptin (LEP) and leptin receptor (LEPR) SNPs on habitual physical activity (PA) and body composition response to a unilateral, upper body resistance training (RT) program.
European-derived American volunteers (men=111, women=131, 23.4±5.4 yr, 24.4±4.6 kg·m−2) were genotyped for LEP 19 G>A (rs2167270), and LEPR 326 A>G (rs1137100), 668 A>G (rs1137101), 3057 G>A (rs1805096), and 1968 G>C (rs8179183). They completed the Paffenbarger PA Questionnaire. Arm muscle and subcutaneous fat volumes were measured before and after 12wk of supervised RT with MRI. Multivariate and repeated measures ANCOVA tested differences among phenotypes by genotype and gender with age and body mass index as covariates.
Adults with the LEP 19 GG genotype reported more kcal/wk in vigorous intensity PA (1273.3±176.8, p=0.017) and sports/recreation (1922.8±226.0, p<0.04) than A allele carriers (718.0±147.2, 1328.6±188.2, respectively). Those with the LEP 19 GG genotype spent more hr/wk in light intensity PA (39.7±1.6) than A allele carriers (35.0±1.4, p=0.03). In response to RT, adults with the LEPR 668 G allele gained greater arm muscle volume (67687.05±3186.7 vs. 52321.87±5125.05 mm3, p=0.01) and subcutaneous fat volume (10599.89±3683.57 vs. −5224.73±5923.98 mm3, p=0.02) than adults with the LEPR 668 AA genotype, respectively.
LEP19 G>A and LEPR 668 A>G associated with habitual PA and the body composition response to RT. These LEP and LEPR SNPs are located in coding exons likely influencing LEP and LEPR function. Further investigation is needed to confirm our findings and establish mechanisms for LEP and LEPR genotype and PA and body composition associations we observed.
PMCID: PMC3500611  PMID: 22975643
exercise; genomics; polymorphism
9.  Protective Effect of CRHR1 Gene Variants on the Development of Adult Depression Following Childhood Maltreatment 
Archives of general psychiatry  2009;66(9):978-985.
A previous study reported a gene × environment interaction in which a haplotype in the corticotropin-releasing hormone receptor 1 gene (CRHR1) was associated with protection against adult depressive symptoms in individuals who were maltreated as children (as assessed by the Childhood Trauma Questionnaire [CTQ]).
To replicate the interaction between childhood maltreatment and a TAT haplotype formed by rs7209436, rs110402, and rs242924 in CRHR1, predicting adult depression.
Two prospective longitudinal cohort studies.
England and New Zealand.
Participants in the first sample were women in the E-Risk Study (N= 1116), followed up to age 40 years with 96% retention. Participants in the second sample were men and women in the Dunedin Study (N= 1037), followed up to age 32 years with 96% retention.
Main Outcome Measure
Research diagnoses of pastyear and recurrent major depressive disorder.
In the E-Risk Study, the TAT haplotype was associated with a significant protective effect. In this effect, women who reported childhood maltreatment on the CTQ were protected against depression. In the Dunedin Study, which used a different type of measure of maltreatment, this finding was not replicated.
A haplotype in CRHR1 has been suggested to exert a protective effect against adult depression among research participants who reported maltreatment on the CTQ, a measure that elicits emotional memories. This suggests the hypothesis that CRHR1’s protective effect may relate to its function in the consolidation of memories of emotionally arousing experiences.
PMCID: PMC3750953  PMID: 19736354
10.  Correction: Genetics of Callous-Unemotional Behavior in Children 
PLoS ONE  2013;8(7):10.1371/annotation/0b16418f-ceb5-41b2-be2a-a20f0c56f9a6.
PMCID: PMC3716723
11.  Genetics of Callous-Unemotional Behavior in Children 
PLoS ONE  2013;8(7):e65789.
Callous-unemotional behavior (CU) is currently under consideration as a subtyping index for conduct disorder diagnosis. Twin studies routinely estimate the heritability of CU as greater than 50%. It is now possible to estimate genetic influence using DNA alone from samples of unrelated individuals, not relying on the assumptions of the twin method. Here we use this new DNA method (implemented in a software package called Genome-wide Complex Trait Analysis, GCTA) for the first time to estimate genetic influence on CU. We also report the first genome-wide association (GWA) study of CU as a quantitative trait. We compare these DNA results to those from twin analyses using the same measure and the same community sample of 2,930 children rated by their teachers at ages 7, 9 and 12. GCTA estimates of heritability were near zero, even though twin analysis of CU in this sample confirmed the high heritability of CU reported in the literature, and even though GCTA estimates of heritability were substantial for cognitive and anthropological traits in this sample. No significant associations were found in GWA analysis, which, like GCTA, only detects additive effects of common DNA variants. The phrase ‘missing heritability’ was coined to refer to the gap between variance associated with DNA variants identified in GWA studies versus twin study heritability. However, GCTA heritability, not twin study heritability, is the ceiling for GWA studies because both GCTA and GWA are limited to the overall additive effects of common DNA variants, whereas twin studies are not. This GCTA ceiling is very low for CU in our study, despite its high twin study heritability estimate. The gap between GCTA and twin study heritabilities will make it challenging to identify genes responsible for the heritability of CU.
PMCID: PMC3706442  PMID: 23874384
12.  Correction: First Genome-Wide Association Study on Anxiety-Related Behaviours in Childhood 
PLoS ONE  2013;8(6):10.1371/annotation/d320e3eb-ab8f-43ce-b341-3da36cd7ff99.
PMCID: PMC3755120
13.  First Genome-Wide Association Study on Anxiety-Related Behaviours in Childhood 
PLoS ONE  2013;8(4):e58676.
Twin studies have shown that anxiety in a general population sample of children involves both domain-general and trait-specific genetic effects. For this reason, in an attempt to identify genes responsible for these effects, we investigated domain-general and trait-specific genetic associations in the first genome-wide association (GWA) study on anxiety-related behaviours (ARBs) in childhood.
The sample included 2810 7-year-olds drawn from the Twins Early Development Study (TEDS) with data available for parent-rated anxiety and genome-wide DNA markers. The measure was the Anxiety-Related Behaviours Questionnaire (ARBQ), which assesses four anxiety traits and also yields a general anxiety composite. Affymetrix GeneChip 6.0 DNA arrays were used to genotype nearly 700,000 single-nucleotide polymorphisms (SNPs), and IMPUTE v2 was used to impute more than 1 million SNPs. Several GWA associations from this discovery sample were followed up in another TEDS sample of 4804 children. In addition, Genome-wide Complex Trait Analysis (GCTA) was used on the discovery sample, to estimate the total amount of variance in ARBs that can be accounted for by SNPs on the array.
No SNP associations met the demanding criterion of genome-wide significance that corrects for multiple testing across the genome (p<5×10−8). Attempts to replicate the top associations did not yield significant results. In contrast to the substantial twin study estimates of heritability which ranged from 0.50 (0.03) to 0.61 (0.01), the GCTA estimates of phenotypic variance accounted for by the SNPs were much lower 0.01 (0.11) to 0.19 (0.12).
Taken together, these GWAS and GCTA results suggest that anxiety – similar to height, weight and intelligence − is affected by many genetic variants of small effect, but unlike these other prototypical polygenic traits, genetic influence on anxiety is not well tagged by common SNPs.
PMCID: PMC3614558  PMID: 23565138
14.  Impact of Selection of Cord Blood Units from the United States and Swiss Registries on the Cost of Banking Operations 
Over the last 2 decades, cord blood (CB) has become an important source of blood stem cells. Clinical experience has shown that CB is a viable source for blood stem cells in the field of unrelated hematopoietic blood stem cell transplantation.
Studies of CB units (CBUs) stored and ordered from the US (National Marrow Donor Program (NMDP) and Swiss (Swiss Blood Stem Cells (SBSQ)) CB registries were conducted to assess whether these CBUs met the needs of transplantation patients, as evidenced by units being selected for transplantation. These data were compared to international banking and selection data (Bone Marrow Donors Worldwide (BMDW), World Marrow Donor Association (WMDA)). Further analysis was conducted on whether current CB banking practices were economically viable given the units being selected from the registries for transplant. It should be mentioned that our analysis focused on usage, deliberately omitting any information about clinical outcomes of CB transplantation.
A disproportionate number of units with high total nucleated cell (TNC) counts are selected, compared to the distribution of units by TNC available. Therefore, the decision to use a low threshold for banking purposes cannot be supported by economic analysis and may limit the economic viability of future public CB banking.
We suggest significantly raising the TNC level used to determine a bankable unit. A level of 125 × 107 TNCs, maybe even 150 × 107 TNCs, might be a viable banking threshold. This would improve the return on inventory investments while meeting transplantation needs based on current selection criteria.
PMCID: PMC3635979  PMID: 23637645
Blood products; CD34+ cells; Collection efficiency; Cord blood; Cost-benefit analysis; Cost-effectiveness analysis; Cryopreservation; Health economics; Hematopoietic cell transplantation; Hematopoietic stem cells
15.  The influence of maternal effects on indirect benefits associated with polyandry 
Despite numerous and diverse theoretical models for the indirect benefits of polyandry, empirical support is mixed. One reason for the difficulty in detecting indirect benefits of polyandry may be that these are subtle and are mediated by environmental effects, such as maternal effects. Maternal effects may be especially important if females allocate resources to their offspring depending on the characteristics of their mating partners. We test this hypothesis in the burying beetle Nicrophorus vespilloides, a species that provides extensive and direct parental care to offspring. We used a fully factorial design and mated females to one, two, three, four or five different males and manipulated conditions so that their offspring received reduced (12 h) or full (ca 72 h) maternal care. We found that average offspring fitness increased with full maternal care but there was no significant effect of polyandry or the interaction between the duration of maternal care and the level of polyandry on offspring fitness. Thus, although polyandry could provide a mechanism for biasing paternity towards high quality or compatible males, and variation in parental care matters, we found no evidence that female N. vespilloides gain indirect benefits by using parental care to bias the allocation of resources under different mating conditions.
PMCID: PMC3049072  PMID: 20926439
burying beetles; indirect benefits; maternal effects; Nicrophorus vespilloides; parental care; polyandry
16.  Absence of Mitochondrial Progesterone Receptor Polymorphisms in Women With Spontaneous Preterm Birth 
The truncated mitochondrial progesterone receptor (PR-M) is homologous to nuclear PRs with the exception of an amino terminus hydrophobic membrane localization sequence, which localizes PR-M to mitochondria. Given the matrilineal inheritance of both spontaneous preterm birth (SPTB) and the mitochondrial genome, we hypothesized that (a) PR-M is polymorphic and (b) PR-M localization sequence polymorphisms could result in variable progesterone mitochondrial effects and variable responsiveness to progesterone prophylaxis.
Secondary analysis of DNA from women enrolled in a multicenter, prospective, study of 17 alpha-hydroxyprogesterone caproate (17OHPC) versus placebo for the prevention of recurrent SPTB. DNA was extracted from stored saliva.
The PR-M localization sequence was sequenced on 344 patients. Sequences were compared with the previously published 48 base-pair sequence, and all were identical.
We did not detect genetic variation in the mitochondrial localization sequence of the truncated PR-M in a group of women at high risk for SPTB.
PMCID: PMC3210024  PMID: 20693499
mitochondria; prematurity; progesterone
17.  Elder Financial Exploitation: Implications for Future Policy and Research in Elder Mistreatment 
Recent advances in the understanding of elder mistreatment have demonstrated that financial exploitation tends to be one of the most common forms of mistreatment affecting older populations. Agencies such as the World Bank and World Health Organization show significant concern regarding financial exploitation and its connection to physical and emotional injury to victims. The World Bank uses the term “financial violence” as a means of generally describing the harm caused to an individual as a result of financial exploitation or abuse. The proportion of financial exploitation in relation to other forms of elder mistreatment is defined in our research. We discuss the potential impact of elder financial exploitation on victims as well as explore the implications for future research and policy development focused on financial aspects of elder mistreatment and call for further study in the concept of financial exploitation as a violent act.
PMCID: PMC3117613  PMID: 21731794
18.  Modulation of ATP-induced Calcium Signaling by progesterone in T47D-Y Breast Cancer Cells 
Molecular and cellular endocrinology  2010;319(1-2):109-115.
Extracellular ATP activates purinergic (P2) receptors with an increase in intracellular calcium and phosphorylation of MAPK. In this study we have investigated the effect of progesterone/progestin on ATP-induced calcium mobilization and phosphorylation of the kinase ERK in the T47D-Y breast cancer cell line that exhibits no detectable nuclear progesterone receptor expression. Brief pretreatment with progesterone/progestin results in a dose dependent inhibition of ATP-induced intracellular calcium mobilization, and inhibition of ERK phosphorylation. Response to a cell impermeable ligand and inhibition of the response by an inactivating antibody suggests a mechanism of action at the plasma membrane. These results in T47D-Y cells strongly suggest that progesterone can act in a rapid non-nuclear manner to inhibit extracellular ATP effects on intracellular calcium mobilization and ERK activation. This research provides an example of progesterone action in a breast cancer cell line lacking expression of the classical nuclear progesterone receptors.
PMCID: PMC2837125  PMID: 20079401
purinergic; progesterone; T47D-Y breast cancer cells; ATP
19.  Novel retrotransposed imprinted locus identified at human 6p25 
Nucleic Acids Research  2011;39(13):5388-5400.
Differentially methylated regions (DMRs) are stable epigenetic features within or in proximity to imprinted genes. We used this feature to identify candidate human imprinted loci by quantitative DNA methylation analysis. We discovered a unique DMR at the 5′-end of FAM50B at 6p25.2. We determined that sense transcripts originating from the FAM50B locus are expressed from the paternal allele in all human tissues investigated except for ovary, in which expression is biallelic. Furthermore, an antisense transcript, FAM50B-AS, was identified to be monoallelically expressed from the paternal allele in a variety of tissues. Comparative phylogenetic analysis showed that FAM50B orthologs are absent in chicken and platypus, but are present and biallelically expressed in opossum and mouse. These findings indicate that FAM50B originated in Therians after divergence from Prototherians via retrotransposition of a gene on the X chromosome. Moreover, our data are consistent with acquisition of imprinting during Eutherian evolution after divergence of Glires from the Euarchonta mammals. FAM50B expression is deregulated in testicular germ cell tumors, and loss of imprinting occurs frequently in testicular seminomas, suggesting an important role for FAM50B in spermatogenesis and tumorigenesis. These results also underscore the importance of accounting for parental origin in understanding the mechanism of 6p25-related diseases.
PMCID: PMC3141237  PMID: 21421564
20.  Regulation of Net Hepatic Glycogenolysis and Gluconeogenesis during Exercise: Impact of Type 1 Diabetes 
The effects of type 1 diabetes on the contributions of net hepatic glycogenolysis and gluconeogenesis to glucose production (GP) at rest and during moderate (MOD) and high (HI) intensity running were examined in healthy control (n = 6) and type 1 diabetic (n = 5) subjects matched for age, weight, and maximum aerobic capacity by combined noninvasive measurements of hepatic glycogen content using 13C nuclear magnetic resonance spectroscopy and determination of GP using [6,6-2H2]glucose. In the control subjects, GP increased in proportion to the intensity of the exercise [at rest (REST), 14.3 ± 0.5; MOD, 18.1 ± 0.9; HI, 28.8 ± 1.3 μmol/(kg-min); P = 0.001, three-way comparison], and this was accounted for by an increase in the percent contribution of net hepatic glycogenolysis to GP (REST, 32 ± 1%; MOD, 49 ± 5%; HI, 57 ± 5%; P = 0.006). In the diabetic subjects, resting rates of GP were 60% higher than those in the control subjects (P < 0.0001) and increased in proportion to the workload. In contrast, the contributions of net hepatic glycogenolysis to GP were consistently lower than those in the control subjects (REST, 20 ± 6%; MOD, 32 ± 13%; HI, 32 ± 3%; P = 0.006 vs. control), and the exaggerated rates of GP could be entirely accounted for by increased rates of gluconeogenesis. In conclusion, 1) increases in GP in healthy control subjects with exercise intensity can be entirely attributed to increases in net hepatic glycogenolysis. 2) In contrast, moderately controlled type 1 diabetic subjects exhibit increased rates of GP both at rest and during exercise, which can be entirely accounted for by increased gluconeogenesis.
PMCID: PMC2995531  PMID: 15356077
21.  AKT1 polymorphisms are associated with risk for metabolic syndrome 
Human Genetics  2010;129(2):129-139.
Converging lines of evidence suggest that AKT1 is a major mediator of the responses to insulin, insulin-like growth factor 1 (IGF1), and glucose. AKT1 also plays a key role in the regulation of both muscle cell hypertrophy and atrophy. We hypothesized that AKT1 variants may play a role in the endophenotypes that make up metabolic syndrome. We studied a 12-kb region including the first exon of the AKT1 gene for association with metabolic syndrome-related phenotypes in four study populations [FAMUSS cohort (n = 574; age 23.7 ± 5.7 years), Strong Heart Study (SHS) (n = 2,134; age 55.5 ± 7.9 years), Dynamics of Health, Aging and Body Composition (Health ABC) (n = 3,075; age 73.6 ± 2.9 years), and Studies of a Targeted Risk Reduction Intervention through Defined Exercise (STRRIDE) (n = 175; age 40–65 years)]. We identified a three SNP haplotype that we call H1, which represents the ancestral alleles at the three loci and H2, which represents the derived alleles at the three loci. In young adult European Americans (FAMUSS), H1 was associated with higher fasting glucose levels in females. In middle age Native Americans (SHS), H1 carriers showed higher fasting insulin and HOMA in males, and higher BMI in females. In older African-American and European American subjects (Health ABC) H1 carriers showed a higher incidence of metabolic syndrome. Homozygotes for the H1 haplotype showed about twice the risk of metabolic syndrome in both males and females (p < 0.001). In middle-aged European Americans with insulin resistance (STRRIDE) studied by intravenous glucose tolerance test (IVGTT), H1 carriers showed increased insulin resistance due to the Sg component (p = 0.021). The 12-kb haplotype is a risk factor for metabolic syndrome and insulin resistance that needs to be explored in further populations.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-010-0910-8) contains supplementary material, which is available to authorized users.
PMCID: PMC3020305  PMID: 21061022
22.  Genotype–environment correlations: implications for determining the relationship between environmental exposures and psychiatric illness 
Psychiatry  2008;7(12):496-499.
Psychosocial risk factors for psychiatric illness are moderately heritable. This has two implications: first, that individuals actively shape their environments through heritable behaviour; second, that the relationship between environmental exposure and psychopathology may be confounded by genotype. We define three types of genotype–environment correlation (passive, evocative, and active), describe the evidence from quantitative and molecular genetic studies for their existence, and discuss the implications of genotype–environment correlations for the prevention and treatment of psychiatric disorder. Research designs are needed that can test which exposures have truly causal effects on mental illness and which are confounded by genotype, so that clinicians can make informed decisions about when modifying exposures will be likely to result in reductions in mental illness. By considering bi-directional and reciprocal relations between risk exposures and patients’ behaviour, clinicians may develop a fuller picture of the causes of disorder and develop more effective treatment methods.
PMCID: PMC2900804  PMID: 20622930
Behavioural genetics; gene-environment correlation; gene-environment interplay; genetic epidemiology; twin studies
23.  Granulocyte Transfusion Therapy: A New Era? 
PMCID: PMC2674763  PMID: 19057197
Neutropenia; Granulocyte transfusions; Severe fungal infections; Granulocyte colony-stimulating factor
24.  A case of unrecognized female epispadias 
Fertility and sterility  2008;90(5):2017.e1-2017.e3.
To present a case of unrecognized female epispadias
Case Report
University-based reproductive endocrinology and fertility clinic
A 16-year-old female with epispadias, history of mild urinary incontinence, auditory neuropathy and functional hyperandrogenism
Main Outcome Measure
Peripheral blood array-based comparative genomic hybridization (array CGH)
The patient was referred for evaluation of excessive weight gain, secondary amenorrhea and abnormal external genitalia. Examination under anesthesia revealed bilateral labia minora hypertrophy, bifid clitoris and a patulous urethra, consistent with female epispadias. Hormonal evaluation showed functional hyperandrogenism while peripheral blood array-based comparative genomic hybridization (array CGH) showed no chromosomal deletions or duplications.
Female epispadias is a rare abnormality, not commonly recognized by most practitioners. The diagnosis is supported by a history of urinary incontinence and physical findings of bifid clitoris and patulous urethra. The condition can have serious physical and psychological consequences leading to a gross disruption of social function.
PMCID: PMC2588430  PMID: 18314106
epispadias; bifid clitoris; urinary incontinence; patulous urethra
25.  Concept, Design and Implementation of a Cardiovascular Gene-Centric 50 K SNP Array for Large-Scale Genomic Association Studies 
PLoS ONE  2008;3(10):e3583.
A wealth of genetic associations for cardiovascular and metabolic phenotypes in humans has been accumulating over the last decade, in particular a large number of loci derived from recent genome wide association studies (GWAS). True complex disease-associated loci often exert modest effects, so their delineation currently requires integration of diverse phenotypic data from large studies to ensure robust meta-analyses. We have designed a gene-centric 50 K single nucleotide polymorphism (SNP) array to assess potentially relevant loci across a range of cardiovascular, metabolic and inflammatory syndromes. The array utilizes a “cosmopolitan” tagging approach to capture the genetic diversity across ∼2,000 loci in populations represented in the HapMap and SeattleSNPs projects. The array content is informed by GWAS of vascular and inflammatory disease, expression quantitative trait loci implicated in atherosclerosis, pathway based approaches and comprehensive literature searching. The custom flexibility of the array platform facilitated interrogation of loci at differing stringencies, according to a gene prioritization strategy that allows saturation of high priority loci with a greater density of markers than the existing GWAS tools, particularly in African HapMap samples. We also demonstrate that the IBC array can be used to complement GWAS, increasing coverage in high priority CVD-related loci across all major HapMap populations. DNA from over 200,000 extensively phenotyped individuals will be genotyped with this array with a significant portion of the generated data being released into the academic domain facilitating in silico replication attempts, analyses of rare variants and cross-cohort meta-analyses in diverse populations. These datasets will also facilitate more robust secondary analyses, such as explorations with alternative genetic models, epistasis and gene-environment interactions.
PMCID: PMC2571995  PMID: 18974833

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