Leveraging linkage evidence to identify low-frequency and rare variants on 16p13 associated with blood pressure using TOPMed whole genome sequencing data

In this study, we investigated low-frequency and rare variants associated with blood pressure (BP) by focusing on a linkage region on chromosome 16p13. We used whole genome sequencing (WGS) data obtained through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program on 395 Cleveland Family Study (CFS) European Americans (CFS-EA). By analyzing functional coding variants and non-coding rare variants with CADD score > 10 residing within the chromosomal region in families with linkage evidence, we observed 25 genes with nominal statistical evidence (burden or SKAT p < 0.05). One of the genes is RBFOX1, an evolutionarily conserved RNA-binding protein that regulates tissue-specific alternative splicing that we previously reported to be associated with BP using exome array data in CFS. After follow-up analysis of the 25 genes in ten independent TOPMed studies with individuals of European, African, and East Asian ancestry, and Hispanics (N = 29,988), we identified variants in SLX4 (p = 2.19 × 10−4) to be significantly associated with BP traits when accounting for multiple testing. We also replicated the associations previously reported for RBFOX1 (p = 0.007). Follow-up analysis with GTEx eQTL data shows SLX4 variants are associated with gene expression in coronary artery, multiple brain tissues, and right atrial appendage of the heart. Our study demonstrates that linkage analysis of family data can provide an efficient approach for detecting rare variants associated with complex traits in WGS data

Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles

Genome-wide association analyses identify 123 susceptibility loci for migraine and implicate neurovascular mechanisms in its pathophysiology. Subtype analyses highlight risk loci specific for migraine with or without aura in addition to shared risk variants.Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.Clinical epidemiolog

Is (poly-) substance use associated with impaired inhibitory control? A mega-analysis controlling for confounders.

Many studies have reported that heavy substance use is associated with impaired response inhibition. Studies typically focused on associations with a single substance, while polysubstance use is common. Further, most studies compared heavy users with light/non-users, though substance use occurs along a continuum. The current mega-analysis accounted for these issues by aggregating individual data from 43 studies (3610 adult participants) that used the Go/No-Go (GNG) or Stop-signal task (SST) to assess inhibition among mostly "recreational" substance users (i.e., the rate of substance use disorders was low). Main and interaction effects of substance use, demographics, and task-characteristics were entered in a linear mixed model. Contrary to many studies and reviews in the field, we found that only lifetime cannabis use was associated with impaired response inhibition in the SST. An interaction effect was also observed: the relationship between tobacco use and response inhibition (in the SST) differed between cannabis users and non-users, with a negative association between tobacco use and inhibition in the cannabis non-users. In addition, participants' age, education level, and some task characteristics influenced inhibition outcomes. Overall, we found limited support for impaired inhibition among substance users when controlling for demographics and task-characteristics

New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475,000 Individuals

Background - Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association. Methods and Results - Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5×10-8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant. Conclusions - We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up

Morning cortisol does not mediate the association of size at birth with blood pressure in children born from full-term pregnancies.

OBJECTIVE: It had been suggested that programming of the hypothalamo-pituitary-adrenal axis may underlie the associations of reduced size at birth with raised blood pressure in later life. We investigated whether morning salivary cortisol mediates the inverse association of birthweight with systolic blood pressure in children. DESIGN: Subjects and measurements--a historical cohort study involving 1152 Swedish children aged 5-14 years, who took part in a family study comprised of mother, father, and two full-sibs delivered in 1987-1995 after 38-41 weeks gestation within 36 months of each other. Birthweight and gestational age were available from obstetric records. Blood pressure, weight, height and puberty stage were measured at a clinic. Cortisol was measured by radioimmunoassay in morning salivary samples taken at home, within 30 min of waking. RESULTS: Morning cortisol showed a weak negative association with length of gestation in siblings, was not related to birthweight or to systolic or diastolic blood pressure. There was no change in the strength of the negative association between birthweight and systolic blood pressure on adjustment for cortisol (-1.4 mmHg/kg, 95% CI -2.7, -0.2; adjusted for age, sex, puberty stage, weight and height, and cortisol). CONCLUSIONS: Morning cortisol was not associated with size at birth, and did not mediate the birthweight-blood pressure association in children born from full-term pregnancies. It is possible that basal cortisol levels are of more importance in explaining associations of size at birth with later blood pressure in older subjects, or in populations with more varied length of gestation. Alternatively, our results may be caused by misclassification of the hypothalamo-pituitary-adrenal activity

Control of polarization and dipole moment in low-dimensional semiconductor nanostructures

We demonstrate the control of polarization and dipole moment in semiconductor nanostructures, through nanoscale engineering of shape and composition. Rodlike nanostructures, elongated along the growth direction, are obtained by molecular beam epitaxial growth. By varying the aspect ratio and compositional contrast between the rod and the surrounding matrix, we rotate the polarization of the dominant interband transition from transverse-electric to transverse-magnetic, and modify the dipole moment producing a radical change in the voltage dependence of absorption spectra. This opens the way to the optimization of quantum dot amplifiers and electro-optical modulators. © 2009 American Institute of Physics

Twin photons from small quantum dots

Due to the large energy splitting of the single-electron levels in a small quantum dot, only one single electron level and one single hole level can be made resonant with the levels in the conduction bandand valence band. This results in a closed system with nine distinct levels, which are split by the Coulomb interactions. We show that flat and tall cylindrically symmetric dots have level schemeswith different selection rules. In both cases entangled photon pairs can be efficiently produced

Dipole orientation in a Quantum Rod

Field-dependent photo-current measurements in Quantum Rod systems show that the orientation of the permanent dipole moment of a standard GaAs/InAs quantum dot can be reversed by fabricating high-aspect ratio Quantum Rod systems. ©2008 IEEE