Structure, Measurement & Analysis of Genetic Variation

Talk given during the "Introduction to Imaging Genetics" workshop at the 2015 Organization for Human Brain Mapping (OHBM) conference in Hawaii, 14-18 June

Structure and Analysis of Genetic Variation

Talk given during the "Introduction to Imaging Genetics" workshop at the 2012 Organization for Human Brain Mapping (OHBM) conference in in Beijing, 10-14 June

Structure and Analysis of Genetic Variation

Talk given during the "Introduction to Imaging Genetics" workshop at the 2013 Organization for Human Brain Mapping (OHBM) conference in Seattle, 16-20 June

Evidence of association between SNPs in <i>FBXL3</i> and bipolar disorder in three independent samples

<p>(WTCCC <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038263#pone.0038263-TheWellcomeTrustCaseControl1" target="_blank">[30]</a>, Sklar et al <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038263#pone.0038263-Sklar1" target="_blank">[31]</a> and Cichon et al <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038263#pone.0038263-Cichon1" target="_blank">[32]</a>).</p

The corticosterone response to the forced swim test.

<p>A significant increase in plasma corticosterone level was seen following the forced swim (F = 160, P<0.0001) but there was no effect of genotype on either corticosterone level at baseline or in response to stress. (Data shown is mean ± SEM).</p

Immobility in the forced swim test is attenuated in after hours mice.

<p>Results from the forced swim test indicate no significant difference in immobility in trial 1 but the increase in immobility observed in trial 2 was not seen in <i>Afh/Afh</i> mice. (Data shown is mean ± SEM). **, <i>P</i><0.01 results from posthoc t-tests comparing immobility in trial 1 <i>vs.</i> trial 2 in <i>Afh/Afh. Afh</i>/+ and +/+ mice.</p

Anxiety-like behaviour is lower in after hours mice.

<p>In the open field test (A-D) <i>Afh</i>/<i>Afh</i> mice entered the central zone more frequently and spent more time there but did not differ in activity measures of speed and distance in the outer zone. In the light-dark box (E–H) <i>Afh</i>/<i>Afh</i> mice entered the light compartment more often and spent more time there and had increased speed in the dark compartment but did not differ in distance travelled in the dark compartment. In the elevated plus maze (I-L), <i>Afh</i>/<i>Afh</i> mice spent more time in the open arms but did not differ in their frequency of entry or closed arm activity measures. (Data shown is mean ± SEM). **<i>P</i><0.01, *<i>P</i><0.05, ^#<i>P</i> = 0.06; effects of genotype in posthoc t-tests (<i>Afh</i>/<i>Afh vs. Afh</i>/+ and +/+<i>)</i>.</p

The effect of after hours genotype on exploratory and anxiety-like behaviour in the holeboard.

<p>Results from the holeboard test indicate no difference in exploratory behaviours (A–B) or overall activity (C–D). <i>Afh</i>/<i>Afh</i> mice spent more time in the centre (E) but did not differ in their number of entries (F). (Data shown is mean ± SEM). **, <i>P</i><0.01 effects of genotype in posthoc t-tests (<i>Afh</i>/<i>Afh vs. Afh</i>/+ and +/+<i>)</i>.</p

Unadjusted SNP p-values for SNPs in FBXL3 reaching significance p<0.05 in at least one study.

<p>Unadjusted SNP p-values for SNPs in FBXL3 reaching significance p<0.05 in at least one study.</p

Enzymatic Assays for the Diagnosis of Bradykinin-Dependent Angioedema

<div><p>Background</p><p>The kinins (primarily bradykinin, BK) represent the mediators responsible for local increase of vascular permeability in hereditary angioedema (HAE), HAE I-II associated with alterations of the <i>SERPING1</i> gene and HAE with normal C1-Inhibitor function (HAE-nC1INH). Besides C1-Inhibitor function and concentration, no biological assay of kinin metabolism is actually available to help physicians for the diagnosis of angioedema (AE). We describe enzymatic tests on the plasma for diagnosis of BK-dependent AE.</p><p>Methods</p><p>The plasma amidase assays are performed using the Pro-Phe-Arg-<i>p</i>-nitroanilide peptide substrate to evaluate the spontaneous amidase activity and the proenzyme activation. We analyzed data of 872 patients presenting with BK-dependent AE or BK-unrelated diseases, compared to 303 controls. Anti-high MW kininogen (HK) immunoblot was achieved to confirm HK cleavage in exemplary samples. Reproducibility, repeatability, limit of blank, limit of detection, precision, linearity and receiver operating characteristics (ROC) were used to calculate the diagnostic performance of the assays.</p><p>Results</p><p>Spontaneous amidase activity was significantly increased in all BK-dependent AE, associated with the acute phase of disease in HAE-nC1INH, but preserved in BK-unrelated disorders. The increase of the amidase activity was associated to HK proteolysis, indicating its relevance to identify kininogenase activity. The oestrogens, known for precipitating AE episodes, were found as triggers of enzymatic activity. Calculations from ROC curves gave the optimum diagnostic cut-off for women (9.3 nmol⋅min⁻¹⋅mL⁻¹, area under curve [AUC] 92.1%, sensitivity 80.0%, and specificity 90.1%) and for men (6.6 nmol·min⁻¹⋅mL⁻¹, AUC 91.0%, sensitivity 87.0% and specificity 81.2%).</p><p>Conclusion</p><p>The amidase assay represents a diagnostic tool to help physicians in the decision to distinguish between BK-related and –unrelated AE.</p></div