Joanne Knight

Genome-wide mapping of human loci for essential hypertension

BACKGROUND Blood pressure may contribute to 50% of the global cardiovascular disease epidemic. By understanding the genes predisposing to common disorders such as human essential hypertension we may gain insights into novel pathophysiological mechanisms and potential therapeutic targets. In the Medical Research Council BRItish Genetics of HyperTension (BRIGHT) study, we aim to identify these genetic factors by scanning the human genome for susceptibility genes for essential hypertension. We describe the results of a genome scan for hypertension in a large white European population. METHODS We phenotyped 2010 affected sibling pairs drawn from 1599 severely hypertensive families, and completed a 10 centimorgan genome-wide scan. After rigorous quality control, we analysed the genotypic data by non-parametric linkage, which tests whether genes are shared in excess among the affected sibling pairs. Lod scores, calculated at regular points along each chromosome, were used to assess the support for linkage. FINDINGS Linkage analysis identified a principle locus on chromosome 6q, with a lod score of 3.21 that attained genome-wide significance (p=0.042). The inclusion of three further loci with lod scores higher than 1.57 (2q, 5q, and 9q) also show genome-wide significance (p=0.017) when assessed under a locus-counting analysis. INTERPRETATION These findings imply that human essential hypertension has an oligogenic element (a few genes may be involved in determination of the trait) possibly superimposed on more minor genetic effects, and that several genes may be tractable to a positional cloning strategy.

Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk.

Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure–raising genetic variants on future cardiovascular disease risk.

Reproductive risk factors and oestrogen/progesterone receptor-negative breast cancer in the Breast Cancer Family Registry

Background:Oestrogen receptor (ER)- and progesterone receptor (PR)-negative (ER−PR−) breast cancer is associated with poorer prognosis compared with other breast cancer subtypes. High parity has been associated with an increased risk of ER−PR− cancer, but emerging evidence suggests that breastfeeding may reduce this risk. Whether this potential breastfeeding benefit extends to women at high risk of breast cancer remains critical to understand for prevention.Methods:Using population-based ascertained cases (n=4011) and controls (2997) from the Breast Cancer Family Registry, we examined reproductive risk factors in relation to ER and PR status.Results:High parity (⩾3 live births) without breastfeeding was positively associated only with ER−PR− tumours (odds ratio (OR)=1.57, 95% confidence interval (CI), 1.10–2.24); there was no association with parity in women who breastfed (OR=0.93, 95% CI 0.71–1.22). Across all race/ethnicities, associations for ER−PR− cancer were higher among women who did not breastfeed than among women who did. Oral contraceptive (OC) use before 1975 was associated with an increased risk of ER−PR− cancer only (OR=1.32, 95% CI 1.04–1.67). For women who began OC use in 1975 or later there was no increased risk.Conclusions:Our findings support that there are modifiable factors for ER−PR− breast cancer and that breastfeeding in particular may mitigate the increased risk of ER−PR− cancers seen from multiparity.

CYP2A6 Reduced Activity Gene Variants Confer Reduction in Lung Cancer Risk in African American Smokers – Findings from Two Independent Populations

We investigated genetic variation in CYP2A6 in relation to lung cancer risk among African American smokers, a high-risk population. Previously, we found that CYP2A6, a nicotine/nitrosamine metabolism gene, was associated with lung cancer risk in European Americans, but smoking habits, lung cancer risk and CYP2A6 gene variants differ significantly between European and African ancestry populations. Herein, African American ever-smokers, drawn from two independent lung cancer case-control studies, were genotyped for reduced activity CYP2A6 alleles and grouped by predicted metabolic activity. Lung cancer risk in the Southern Community Cohort Study (n = 494) was lower among CYP2A6 reduced versus normal metabolizers, as estimated by multivariate conditional logistic regression [odds ratio (OR) = 0.44; 95% confidence interval (CI) = 0.26-0.73] and by unconditional logistic regression (OR = 0.62; 95% CI = 0.41-0.94). The association was replicated in an independent study from MD Anderson Cancer Center (n = 407) (OR = 0.64; 95% CI = 0.42-0.98), and pooling the studies yielded an OR of 0.64 (95% CI = 0.48-0.86). Exploratory analyses revealed a significant interaction between CYP2A6 genotype and sex on the risk for lung cancer (Southern Community Cohort Study: P = 0.04; MD Anderson: P = 0.03; Pooled studies: P = 0.002) with a CYP2A6 effect in men only. These findings support a contribution of genetic variation in CYP2A6 to lung cancer risk among African American smokers, particularly men, whereby CYP2A6 genotypes associated with reduced metabolic activity confer a lower risk of developing lung cancer.

Pharmacogenetic Analysis of Functional Glutamate System Gene Variants and Clinical Response to Clozapine

Altered glutamate neurotransmission is implicated in the etiology of schizophrenia (SCZ) and the pharmacogenetics of response to clozapine (CLZ), which is the drug of choice for treatment-resistant SCZ. Response to antipsychotic therapy is highly variable, although twin studies suggest a genetic component. We investigated the association of 10 glutamate system gene variants with CLZ response using standard genotyping procedures. GRM2 (rs4067 and rs2518461), SLC1A2 (rs4354668, rs4534557, and rs2901534), SLC6A9 (rs12037805, rs1978195, and rs16831558), GRIA1 (rs2195450), and GAD1 (rs3749034) were typed in 163 European SCZ/schizoaffective disorder patients deemed resistant or intolerant to previous pharmacotherapy. Response was assessed following 6 months of CLZ monotherapy using change in Brief Psychiatric Rating Scale (BPRS) scores. Categorical and continuous response variables were analyzed using χ2 tests and analysis of covariance, respectively. We report no significant associations following correction for multiple testing. Prior to correction, nominally significant associations were observed for SLC6A9, SLC1A2, GRM2, and GRIA1. Most notably, CC homozygotes of rs16831558 located in the glycine transporter 1 gene (SLC6A9) exhibited an allele dose-dependent improvement in positive symptoms compared to T allele carriers (puncorrected = 0.008, pcorrected = 0.08). To clarify the role of SLC6A9 in clinical response to antipsychotic medication, and CLZ in particular, this finding warrants further investigation in larger well-characterized samples.

CEREBRAL PERFUSION AS AN IMAGING BIOMARKER OF PRESYMPTOMATIC GENETIC FRONTOTEMPORAL DEMENTIA: PRELIMINARY RESULTS FROM THE GENETIC FRONTOTEMPORAL DEMENTIA INITIATIVE (GENFI)

Background Frontotemporal dementia (FTD) is a common cause of early onset dementia. While three genetic mutations are responsible for the majority of genetic FTD, imaging biomarkers that predict symptom onset are needed1. Recent work shows volumetric changes several years before the predicted age at disease onset2. Herein, we extend on this work by investigating whether perfusion patterns derived from non-invasive arterial spin labeling (ASL) MRI can be used as an early functional neuroimaging biomarker of presymptomatic genetic FTD. Methods Data were drawn from the GENetic Frontotemporal dementia Initiative (GENFI)2. From the first GENFI data freeze (n=220), 168 subjects had 3T ASL from which this analysis considers only the presymptomatic carriers and controls (n=144, Table 1). Cerebral blood flow (CBF)-maps were scaled to a mean grey matter (GM) CBF of 50 mL/100g/min per ASL sequence (four different ASL sequences were used) and registered to SPM12 3D T1 GM segmentations that were registered to MNI using DARTEL. In pre-selected ROIs associated with FTD, we investigated the effects of mutation status and years to expected age of disease onset on CBF, accounting for gender and family membership as fixed and random covariates. ROI CBF-values were corrected for partial volume fractions. Results Years to expected age of disease onset (p 0.1), there was an interaction effect between mutation carrier status and years to expected age of disease onset on CBF (Table 2). This interaction effect was significant for all ROIs except for the parietal and occipital cortices, anterior cingulate and putamen with the strongest effects being seen in the insula and the caudate nucleus (Figure 1). Conclusions CBF decreased as individuals approached the expected age of disease onset and this CBF decrease was accelerated in the presymptomatic mutation carriers compared to controls, in key regions implicated in FTD. These preliminary findings demonstrate the potential utility of non-invasive perfusion MRI as an early biomarker for genetic FTD. References 1. Montine et al., Neurology 2014 2. Rohrer et al., Lancet Neurol 2015