To determine whether European Americans with polycystic ovary syndrome (PCOS) exhibit genetic differences associated with PCOS status and phenotypic features.
Case-control association study in ...European Americans.
Academic center.
Women with PCOS diagnosed with the use of the National Institutes of Health criteria (n = 532) and control women with regular menstrual cycles and no evidence of hyperandrogenism (n = 432).
Blood was drawn for measurement of sex steroids, metabolic parameters, and genotyping.
Associations among PCOS status, phenotype, and genetic background identified with the use of principal component analysis.
Principal component analysis identified five principal components (PCs). PC1 captured northwest-to-southeast European genetic variation and was associated with PCOS status. Acanthosis was associated with southern European ancestry, and larger waist:hip ratio was associated with northern European ancestry. PC2 was associated with east-to-west European genetic variation and cholesterol levels.
These data provide evidence for genetic influence based on European ethnicity in women with PCOS. There is also evidence for a genetic component in the phenotypic features of PCOS within a mixed European population. The data point to the need to control for population stratification in genetic studies in women of mixed European ethnicity. They also emphasize the need for better studies of PCOS prevalence and phenotype as a function of genetic background.
Mutations in the colony stimulating factor 1 receptor (CSF1R) have recently been discovered as causal for hereditary diffuse leukoencephalopathy with axonal spheroids. We identified a novel, ...heterozygous missense mutation in CSF1R c.1990G > A p.(E664K) by exome sequencing in five members of a family with hereditary diffuse leukoencephalopathy with axonal spheroids. Three affected siblings had characteristic white matter abnormalities and presented with progressive neurological decline. In the fourth affected sibling, early progression halted after allogeneic haematopoietic stem cell transplantation from a related donor. Blood spot DNA from this subject displayed chimerism in CSF1R acquired after haematopoietic stem cell transplantation. Interestingly, both parents were unaffected but the mother's blood and saliva were mosaic for the CSF1R mutation. Our findings suggest that expression of wild-type CSF1R in some cells, whether achieved by mosaicism or chimerism, may confer benefit in hereditary diffuse leukoencephalopathy with axonal spheroids and suggest that haematopoietic stem cell transplantation might have a therapeutic role for this disorder.
The genetic susceptibility to preeclampsia, a pregnancy-specific complication with significant maternal and fetal morbidity, has been poorly characterized. To identify maternal genes associated with ...preeclampsia risk, we assembled 498 cases and 1864 controls of European ancestry from preeclampsia case-control collections in 5 different US sites (with additional matched population controls), genotyped samples on a cardiovascular gene-centric array composed of variants from ≈2000 genes selected based on prior genetic studies of cardiovascular and metabolic diseases and performed case-control genetic association analysis on 27 429 variants passing quality control. In silico replication testing of 9 lead signals with
<10
was performed in independent European samples from the SOPHIA (Study of Pregnancy Hypertension in Iowa) and Inova cohorts (212 cases, 456 controls). Multiethnic assessment of lead signals was then performed in samples of black (26 cases, 136 controls), Hispanic (132 cases, 468 controls), and East Asian (9 cases, 80 controls) ancestry. Multiethnic meta-analysis (877 cases, 3004 controls) revealed a study-wide statistically significant association of the rs9478812 variant in the pleiotropic
gene (odds ratio, 1.40 1.23-1.60;
=5.90×10
). The rs9478812 effect was even stronger in the subset of European cases with known early-onset preeclampsia (236 cases diagnosed <37 weeks, 1864 controls; odds ratio, 1.59 1.27-1.98;
=4.01×10
).
variants have previously been implicated in genome-wide association studies of blood pressure, body weight, and neurological disorders. Although larger studies are required to further define maternal preeclampsia heritability, this study identifies a novel maternal risk locus for further investigation.
The risk of type 2 diabetes (T2D) is increased by abnormalities in sleep quantity and quality, circadian alignment, and melatonin regulation. A common genetic variant in a receptor for the ...circadian-regulated hormone melatonin (MTNR1B) is associated with increased fasting blood glucose and risk of T2D, but whether sleep or circadian disruption mediates this risk is unknown. We aimed to test if MTNR1B diabetes risk variant rs10830963 associates with measures of sleep or circadian physiology in intensive in-laboratory protocols (n = 58-96) or cross-sectional studies with sleep quantity and quality and timing measures from self-report (n = 4,307-10,332), actigraphy (n = 1,513), or polysomnography (n = 3,021). In the in-laboratory studies, we found a significant association with a substantially longer duration of elevated melatonin levels (41 min) and delayed circadian phase of dim-light melatonin offset (1.37 h), partially mediated through delayed offset of melatonin synthesis. Furthermore, increased T2D risk in MTNR1B risk allele carriers was more pronounced in early risers versus late risers as determined by 7 days of actigraphy. Our results provide the surprising insight that the MTNR1B risk allele influences dynamics of melatonin secretion, generating a novel hypothesis that the MTNR1B risk allele may extend the duration of endogenous melatonin production later into the morning and that early waking may magnify the diabetes risk conferred by the risk allele.
Objective
Genetic factors underlying susceptibility to rheumatoid arthritis (RA) in Arab populations are largely unknown. This genome‐wide association study (GWAS) was undertaken to explore the ...generalizability of previously reported RA loci to Arab subjects and to discover new Arab‐specific genetic loci.
Methods
The Genetics of Rheumatoid Arthritis in Some Arab States Study was designed to examine the genetics and clinical features of RA patients from Jordan, the Kingdom of Saudi Arabia, Lebanon, Qatar, and the United Arab Emirates. In total, >7 million single‐nucleotide polymorphisms (SNPs) were tested for association with RA overall and with seropositive or seronegative RA in 511 RA cases and 352 healthy controls. In addition, replication of 15 signals was attempted in 283 RA cases and 221 healthy controls. A genetic risk score of 68 known RA SNPs was also examined in this study population.
Results
Three loci (HLA region, intergenic 5q13, and 17p13 at SMTNL2/GGT6) reached genome‐wide significance in the analyses of association with RA and with seropositive RA, and for all 3 loci, evidence of independent replication was demonstrated. Consistent with the findings in European and East Asian populations, the association of RA with HLA–DRB1 amino acid position 11 conferred the strongest effect (P = 4.8 × 10−16), and a weighted genetic risk score of previously associated RA loci was found to be associated with RA (P = 3.41 × 10−5) and with seropositive RA (P = 1.48 × 10−6) in this population. In addition, 2 novel associations specific to Arab populations were found at the 5q13 and 17p13 loci.
Conclusion
This first RA GWAS in Arab populations confirms that established HLA‐region and known RA risk alleles contribute strongly to the risk and severity of disease in some Arab groups, suggesting that the genetic architecture of RA is similar across ethnic groups. Moreover, this study identified 2 novel RA risk loci in Arabs, offering further population‐specific insights into the pathophysiology of RA.
The sleep electroencephalogram (EEG) is highly heritable in humans and yet little is known about the genetic basis of inter-individual differences in sleep architecture. The aim of this study was to ...identify associations between candidate circadian gene variants and the polysomnogram, recorded under highly controlled laboratory conditions during a baseline, overnight, 8 h sleep opportunity. A candidate gene approach was employed to analyze single-nucleotide polymorphisms from five circadian-related genes in a two-phase analysis of 84 healthy young adults (28 F; 23.21 ± 2.97 years) of European ancestry. A common variant in Period2 (PER2) was associated with 20 min less slow-wave sleep (SWS) in carriers of the minor allele than in noncarriers, representing a 22% reduction in SWS duration. Moreover, spectral analysis in a subset of participants (n = 37) showed the same PER2 polymorphism was associated with reduced EEG power density in the low delta range (0.25-1.0 Hz) during non-REM sleep and lower slow-wave activity (0.75-4.5 Hz) in the early part of the sleep episode. These results indicate the involvement of PER2 in the homeostatic process of sleep. Additionally, a rare variant in Melatonin Receptor 1B was associated with longer REM sleep latency, with minor allele carriers exhibiting an average of 65 min (87%) longer latency from sleep onset to REM sleep, compared to noncarriers. These findings suggest that circadian-related genes can modulate sleep architecture and the sleep EEG, including specific parameters previously implicated in the homeostatic regulation of sleep.
The PERIOD2 (PER2) gene is a core molecular component of the circadian clock and plays an important role in the generation and maintenance of daily rhythms. Rs35333999, a missense variant of PER2 ...common in European populations, has been shown to associate with later chronotype. Chronotype relates to the timing of biological and behavioral activities, including when we sleep, eat, and exercise, and later chronotype is associated with longer intrinsic circadian period (cycle length), a fundamental property of the circadian system. Thus, we tested whether this PER2 variant was associated with circadian period and found significant associations with longer intrinsic circadian period as measured under forced desynchrony protocols, the 'gold standard' for intrinsic circadian period assessment. Minor allele (T) carriers exhibited significantly longer circadian periods when determinations were based on either core body temperature or plasma melatonin measurements, as compared to non-carriers (by 12 and 11 min, respectively; accounting for ~7% of inter-individual variance). These findings provide a possible underlying biological mechanism for inter-individual differences in chronotype, and support the central role of PER2 in the human circadian timing system.
The optical properties of nanoparticles (NPs) near metal surfaces must be better understood in order to fully exploit their signal-enhancing capabilities in optical biosensors, such as in surface ...plasmon resonance studies. We use angle-resolved SPR imaging and a modified Maxwell−Garnett model to determine the optical properties of 10-nm-diameter gold NPs deposited on planar Au coated with various thicknesses of SiO2. We investigate how the intrinsic NP dielectric constants and extinction coefficients vary as a function of particle-to-metal-substrate distance (d P−S) for short distances that span the dimension of the NP (0−26 nm) and as a function of excitation wavelength (λexc) for values that span the NP absorbance spectrum. When the NPs are deposited almost directly onto the Au substrate, the NP dielectric function shows anomalous dispersion. At distances far from the planar Au, normal dispersion is observed. The distance dependence, viewed in terms of extinction coefficients, is consistent with a red shift in the NP absorption as d P−S decreases. Although this shift has been predicted and observed, the distance dependence of the intrinsic NP dielectric function is not known. Indeed, NP dielectric functions, which are exquisitely sensitive to experimental conditions, are generally not available. Such fundamental NP properties are needed for quantitative applications in high-sensitivity refractive-index-based biosensors and may also be useful for testing theoretical models.
Objective: To examine the association between genetic predisposition to elevated C-reactive protein (CRP)and risk for preeclampsia using validated genetic loci for C-reactive protein. Methods: ...Preeclampsia cases (n = 177) and normotensive controls (n = 116) were selected from live birth certificates to nulliparous Iowa women during the period August 2002-May 2005. Disease status was verified by the medical chart review. Genetic predisposition to CRP was estimated by a genetic risk score on the basis of established loci for CRP levels. Logistic regression analyses were used to evaluate the relationships between the genotype score and preeclampsia. Replication analyses were performed in an independent, US population of preeclampsia cases (n = 516) and controls (n = 1,097) of European ancestry. Results: The genetic risk score (GRS) related to higher levels of CRP demonstrated a significantly decreased risk of preeclampsia (OR 0.89, 95% CI 0.82-0.96). When the GRS was analyzed by quartile, an inverse linear trend was observed (p = 0.0006). The results were similar after adjustments for the body mass index (BMI), smoking, and leisure-time physical activity. In the independent replication population, the association with the CRP GRS was also marginally significant (OR 0.97, 95% CI 0.92, 1.02). Meta-analysis of the two studies was statistically significant (OR 0.95, 95% CI 0.90, 0.99). Conclusion: Our data suggest an inverse, counterintuitive association between the genetic predisposition to elevated levels of CRP and a decreased risk of preeclampsia. This suggests that the blood CRP level is a marker of preeclampsia, but it does not appear to be a factor on the causal pathway.
PDF
