Genome-wide association studies: a primer

There have been nearly 400 genome-wide association studies (GWAS) published since 2005. The GWAS approach has been exceptionally successful in identifying common genetic variants that predispose to a variety of complex human diseases and biochemical and anthropometric traits. Although this approach is relatively new, there are many excellent reviews of different aspects of the GWAS method. Here, we provide a primer, an annotated overview of the GWAS method with particular reference to psychiatric genetics. We dissect the GWAS methodology into its components and provide a brief description with citations and links to reviews that cover the topic in detail

Kinematic analysis of an en echelon--continuous vein complex

An array of sigmoidal tension gashes from the Idaho--Wyoming thrust belt changes laterally into a continuous vein. Detailed mechanical twin analysis was used to determine the strain variation in the optically and chemically homogeneous blocky calcite filling. In the continuous portion of the vein complex, the shortening axes are parallel to the vein boundary. However, the orientation of the shortening axes in the tip areas of the sigmoidal gashes are at an angle of approximately 35[deg] to the vein boundary, and are parallel to the trend of the tips. Twinning patterns in the central portions of the gashes record two principal strain axes of shortening of nearly equal magnitude with the maximum perpendicular to the vein trend. Everywhere in the vein complex the orientation of the maximum extension axis is parallel to the twist axis of the gashes. The petrofabric strain results show that the vein filling has largely recorded local strains. The pattern of variation in orientation of the principal strains in the vein complex is in close agreement with the theoretically determined stress distribution in similar structures. Our results show that the sigmoidal gashes were formed at the leading edge of a propagating vein and that the sigmoidal shape reflects changes in the local strain field rather than a remote shear. The orientation of these local strains closely corresponds to the orientation of the local stresses.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27567/1/0000611.pd

Precise U-Pb zircon ages and geochemistry of Jurassic granites, Ellsworth-Whitmore terrane, central Antarctica

The Ellsworth-Whitmore Mountain terrane of central Antarctica was part of the early Paleozoic amalgamation of Gondwana, including a 13,000 m section of Cambrian–Permian sediments in the Ellsworth Mountains deposited on Grenville-age crust. The Jurassic breakup of Gondwana involved a regional, bimodal magmatic event during which the Ellsworth-Whitmore terrane was intruded by intraplate granites before translation of the terrane to its present location in central Antarctica. Five widely separated granitic plutons in the Ellsworth-Whitmore terrane were analyzed for their whole-rock geochemistry (X-ray fluorescence), Sr, Nd, and Pb isotopic compositions, and U-Pb zircon ages to investigate the origins of the terrane magmas and their relationships to mafic magmatism of the 183 Ma Karoo-Ferrar large igneous province (LIP). We report high-precision (±0.1 m.y.) isotope dilution–thermal ionization mass spectrometry (ID-TIMS) U-Pb zircon ages from granitic rocks from the Whitmore Mountains (208.0 Ma), Nash Hills (177.4–177.3 Ma), Linck Nunatak (175.3 Ma), Pagano Nunatak (174.8 Ma), and the Pirrit Hills (174.3–173.9 Ma), and U-Pb sensitive high-resolution ion microprobe (SHRIMP) ages from the Whitmore Mountains (200 ± 5 Ma), Linck Nunatak (180 ± 4 Ma), Pagano Nunatak (174 ± 4 Ma), and the Pirrit Hills (168 ± 4 Ma). We then compared these results with existing K-Ar ages and Nd model ages, and used initial Sr, Nd, and Pb isotope ratios, combined with xenocrystic zircon U-Pb inheritance, to infer characteristics of the source(s) of the parent magmas. We conclude that the Jurassic plutons were not derived exclusively from crustal melts, but rather they are hybridized magmas composed of convecting mantle, subcontinental lithospheric mantle, and lower continental crustal contributions. The mantle contributions to the granites share isotopic similarities to the sources of other Jurassic LIP mafic magmas, including radiogenic 87Sr/86Sr (0.706–0.708), unradiogenic 143Nd/144Nd (εNd < –5), and Pb isotopes consistent with a low-µ source (where μ = 238U/204Pb). Isotopes and zircon xenocrysts point toward a crustal end member of predominantly Proterozoic provenance (0.5–1.0 Ga; Grenville crust), extending the trends illustrated by Ferrar mafic intrusive rocks, but contrasting with the inferred Archean crustal and/or lithospheric mantle contributions to some basalts of the Karoo sector of the LIP. The Ellsworth-Whitmore terrane granites are the result of mafic rocks underplating the hydrous crust, causing crustal melting, hybridization, and fractionation to produce granitic magmas that were eventually emplaced as post-Ferrar, within-plate melts at higher crustal levels as the Ellsworth-Whitmore terrane rifted off Gondwana (47°S) before migrating to its current position (82°S) in central Antarctica

Volcanic Initiation of the Eocene Heart Mountain Slide, Wyoming, USA

The Eocene Heart Mountain slide of northwest Wyoming covers an area of as much as 5000 km2 and includes allochthonous Paleozoic carbonate and Eocene volcanic rocks with a run-out distance of as much as 85 km. Recent geochronologic data indicated that the emplacement of the slide event occurred at ∼48.9 Ma, using laser ablation inductively coupled plasma mass spectrometry (LA-ICPMS) extracted from U-Pb zircon ages from basal layer and injectite carbonate ultracataclasite (CUC). We now refine that age with U-Pb results from a lamprophyre diatreme that is temporally and spatially related to the CUC injectites. The ages for the lamprophyre zircons are 48.97 ± 0.36 Ma (LA-ICPMS) and 49.19 ±0.02 Ma (chemical abrasion isotope dilution thermal ionization mass spectrometry). Thus, the lamprophyre and CUC zircons are identical in age, and we interpret that the zircons in the CUC were derived from the lamprophyre during slide emplacement. Moreover, the intrusion of the lamprophyre diatreme provided the trigger mechanism for the Heart Mountain slide. Additional structural data are presented for a variety of calcite twinning strains, results from anisotropy of magnetic susceptibility for the lamprophyre and CUC injectites and alternating-field demagnetization on the lamprophyre, to help constrain slide dynamics. These data indicate that White Mountain experienced a rotation about a vertical axis and minimum of 35° of counterclockwise motion during emplacement

Anhysteretic remanent magnetic anisotropy and calcite strains in Devonian carbonates from the Appalachian Plateau, New York

Anisotropy of anhysteretic susceptibility (AAS) is a recently developed high-resolution method of measuring the magnetic fabric of rocks. In order to test the applicability and limitations of AAS for estimation of strain orientations in weakly-deformed and weakly magnetic rocks, we have used the method to examine the magnetic fabric of samples from a series of sites in limestones of the Helderberg and Onondaga formations along a 500-km E-W transect across New York State. Two distinct shortening directions have been previously identified and interpreted in terms of two separate phases of Alleghenian deformation. Over most of the transect, minimum anhysteretic susceptibility axes within the plane of bedding closely parallel the compression direction of the earlier ("Lackawanna") phase. A few sites show minimum anhysteretic susceptibility parallel to the later ("Main") phase. The threshold for resolution of the tectonic signal by AAS is at anhysteretic susceptibilities of about 2 x 10-5 (SI) and strain magnitudes of 0.5 to 1% as recorded by twinning in calcite. The central part of the transect exhibits minimum horizontal anhysteretic susceptibility perpendicular to the inferred tectonic compression, rather than parallel to it. We attribute this to either: (a) anisotropic transmission of stresses from the larger calcite matrix grains to the smaller magnetite grains during twinning; or (b) preferential recording of a late-stage non-coaxial stress direction in this area by late diagenetic magnetite.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27974/1/0000406.pd

Gender differences in the association between adiposity and probable major depression: a cross-sectional study of 140,564 UK Biobank participants

&lt;b&gt;Background&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Previous studies on the association between adiposity and mood disorder have produced contradictory results, and few have used measurements other than body mass index (BMI). We examined the association between probable major depression and several measurements of adiposity: BMI, waist circumference (WC), waist-hip-ratio (WHR), and body fat percentage (BF%).&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methods&lt;/b&gt;&lt;p&gt;&lt;/p&gt; We conducted a cross-sectional study using baseline data on the sub-group of UK Biobank participants who were assessed for mood disorder. Multivariate logistic regression models were used, adjusting for potential confounders including: demographic and life-style factors, comorbidity and psychotropic medication.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Results&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Of the 140,564 eligible participants, evidence of probable major depression was reported by 30,145 (21.5%). The fully adjusted odds ratios (OR) for obese participants were 1.16 (95% confidence interval (CI) 1.12, 1.20) using BMI, 1.15 (95% CI 1.11, 1.19) using WC, 1.09 (95% CI 1.05, 1.13) using WHR and 1.18 (95% CI 1.12, 1.25) using BF% (all p &#60;0.001). There was a significant interaction between adiposity and gender (p = 0.001). Overweight women were at increased risk of depression with a dose response relationship across the overweight (25.0-29.9 kg/m2), obese I (30.0-34.9 kg/m2), II (35.0-39.9 kg/m2) and III (≥40.0 kg/m2) categories; fully adjusted ORs 1.14, 1.20, 1.29 and 1.48, respectively (all p &#60; 0.001). In contrast, only obese III men had significantly increased risk of depression (OR 1.29, 95% CI 1.08, 1.54, p = 0.006).&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusion&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Adiposity was associated with probable major depression, irrespective of the measurement used. The association was stronger in women than men. Physicians managing overweight and obese women should be alert to this increased risk

Heaviness, health and happiness: a cross-sectional study of 163 066 UK Biobank participants

&lt;b&gt;Background&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Obesity is known to increase the risk of many diseases and reduce overall quality of life. This study examines the relationship with self-reported health (SRH) and happiness.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methods&lt;/b&gt; &lt;p&gt;&lt;/p&gt;We conducted a cross-sectional study of the 163 066 UK Biobank participants who completed the happiness rating. The association between adiposity and SRH and happiness was examined using logistic regression. SRH was defined as good (excellent, good), or poor (fair, poor). Self-reported happiness was defined as happy (extremely, very, moderately) or unhappy (moderately, very, extremely). &lt;p&gt;&lt;/p&gt; &lt;b&gt;Results&lt;/b&gt; &lt;p&gt;&lt;/p&gt;Poor health was reported by 44 457 (27.3%) participants. The adjusted ORs for poor health were 3.86, 2.92, 2.60 and 6.41 for the highest, compared with lowest, deciles of Body Mass Index, waist circumference, waist to hip ratio and body fat percent, respectively. The associations were stronger in men (p&lt;0.001). Overall, 7511 (4.6%) participants felt unhappy, and only class III obese participants were more likely to feel unhappy (adjusted OR 1.33, 95% CI 1.15 to 1.53, p&lt;0.001) but the associations differed by sex (p&lt;0.001). Among women, there was a significant association between unhappiness and all levels of obesity. By contrast, only class III obese men had significantly increased risk and overweight and class I obese men were less likely to be unhappy. &lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusions&lt;/b&gt;&lt;p&gt;&lt;/p&gt;Obesity impacts adversely on happiness as well as health, but the association with unhappiness disappeared after adjustment for self-reported health, indicating this may be mediated by health. Compared with obese men, obese women are less likely to report poor health, but more likely to feel unhappy. &lt;p&gt;&lt;/p&gt

Food habits of Sowerby's beaked whales (Mesoplodon bidens) taken in the pelagic drift gillnet fishery of the western North Atlantic

We describe the food habits of the Sowerby’s beaked whale (Mesoplodon bidens) from observations of 10 individuals taken as bycatch in the pelagic drift gillnet fishery for Swordfish (Xiphias gladius) in the western North Atlantic and 1 stranded individual from Kennebunk, Maine. The stomachs of 8 bycaught whales were intact and contained prey. The diet of these 8 whales was dominated by meso- and benthopelagic fishes that composed 98.5% of the prey items found in their stomachs and cephalopods that accounted for only 1.5% of the number of prey. Otoliths and jaws representing at least 31 fish taxa from 15 families were present in the stomach contents. Fishes, primarily from the families Moridae (37.9% of prey), Myctophidae (22.9%), Macrouridae (11.2%), and Phycidae (7.2%), were present in all 8 stomachs. Most prey were from 5 fish taxa: Shortbeard Codling (Laemonema barbatulum) accounted for 35.3% of otoliths, Cocco’s Lanternfish (Lobianchia gemellarii) contributed 12.9%, Marlin-spike (Nezumia bairdii) composed 10.8%, lanternfishes (Lampanyctus spp.) accounted for 8.4%; and Longfin Hake (Phycis chesteri) contributed 6.7%. The mean number of otoliths per stomach was 1196 (range: 327–3452). Most of the fish prey found in the stomachs was quite small, ranging in length from 4.0 to 27.7 cm. We conclude that the Sowerby’s beaked whales that we examined in this study fed on large numbers of relatively small meso- and benthopelagic fishes that are abundant along the slope and shelf break of the western North Atlantic

Re-evaluation of putative rheumatoid arthritis susceptibility genes in the post-genome wide association study era and hypothesis of a key pathway underlying susceptibility

Rheumatoid arthritis (RA) is an archetypal, common, complex autoimmune disease with both genetic and environmental contributions to disease aetiology. Two novel RA susceptibility loci have been reported from recent genome-wide and candidate gene association studies. We, therefore, investigated the evidence for association of the STAT4 and TRAF1/C5 loci with RA using imputed data from the Wellcome Trust Case Control Consortium (WTCCC). No evidence for association of variants mapping to the TRAF1/C5 gene was detected in the 1860 RA cases and 2930 control samples tested in that study. Variants mapping to the STAT4 gene did show evidence for association (rs7574865, P = 0.04). Given the association of the TRAF1/C5 locus in two previous large case–control series from populations of European descent and the evidence for association of the STAT4 locus in the WTCCC study, single nucleotide polymorphisms mapping to these loci were tested for association with RA in an independent UK series comprising DNA from >3000 cases with disease and >3000 controls and a combined analysis including the WTCCC data was undertaken. We confirm association of the STAT4 and the TRAF1/C5 loci with RA bringing to 5 the number of confirmed susceptibility loci. The effect sizes are less than those reported previously but are likely to be a more accurate reflection of the true effect size given the larger size of the cohort investigated in the current study