Cluster headache genome-wide association study and meta-analysis identifies eight loci and implicates smoking as causal risk factor.

OBJECTIVE: Aggregating data for the first genome-wide association study meta-analysis of cluster headache, to identify genetic risk variants and gain biological insights. METHODS: A total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from ten European and one East Asian cohorts. We first performed an inverse-variance genome-wide association meta-analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans-ancestry meta-analysis we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by five complementary methods: expression quantitative trait loci, transcriptome-wide association, fine-mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis and Mendelian randomization were part of the downstream analyses. RESULTS: The estimated SNP-based heritability of cluster headache was 14.5%. We identified nine independent signals in seven genome-wide significant loci in the primary meta-analysis, and one additional locus in the trans-ethnic meta-analysis. Five of the loci were previously known. The 20 genes prioritized as potentially causal for cluster headache showed enrichment to artery and brain tissue. Cluster headache was genetically correlated with cigarette smoking, risk-taking behavior, ADHD, depression and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache. Three of the identified loci were shared with migraine. INTERPRETATION: This first genome-wide association study meta-analysis gives clues to the biological basis of cluster headache and indicates that smoking is a causal risk factor. This article is protected by copyright. All rights reserved

Numerical modelling of Cenozoic stress patterns in the Mid Norwegian Margin and the northern Sea

Numerical modeling of Cenozoic stress patterns in the northern North Sea and the mid-Norwegian margin is presented, and the sense of potential slip along major fault planes belonging to the two areas is restored. We assume that the main regional source of stresses is the Atlantic ridge push as demonstrated by previous studies. Furthermore, we also assume a nearly consistent NW-SE strike for the far-field stress from continental breakup between Greenland and Norway (earliest Eocene) to present day. First, we applied the commercial two-dimensional distinct element method (UDEC) to simulate Cenozoic stress and displacement patterns in the study area. Variations in rheology and major fault zones were introduced into the model. The Møore-Trøondelag Fault Complex and its inferred continuation into the Shetland Platform forms the major mechanical discontinuity in the model. Second, we used the SORTAN method, developed at the University of Paris VI, to predict the sense of potential slip along major fault planes. The input for the SORTAN model was constrained by the geometry of the selected fault planes and local principal stress directions extracted from the UDEC modeling. Our results show that the Møore-Trøondelag Fault Complex and its inferred continuation into the Shetland Platform act as a weak fault zone. This fault zone divides the study area into two different stress provinces: the continental margin and the northern North Sea. This result agrees well with the observed differences in Cenozoic structural evolution of the two areas. Compressive structures are observed along the continental margin, whereas relative tectonic quiescence characterizes the northern North Sea during the Tertiary. The restored stress patterns in the northern North Sea and the mid-Norwegian margin also agree well with the observed present-day stress configuration. Our analysis demonstrates a method to reconstruct the sense of slip on major fault planes by combining two complementary numerical tools (UDEC and SORTAN). As a result, it is demonstrated that oblique-slip motions are mainly expected, in particular, strike-slip and reverse dip-slip faulting are simulated

Mesozoic and Cenozoic tectonics of the More Trondelag Fault Complex, central Norway: constraints from new apatite fission track data

The Møre Trøndelag Fault Complex (MTFC) of central Norway is a long-lived structural zone whose tectonic history included dextral strike slip, sinistral strike slip, and vertical offset. Determination of an offset history for the MTFC is complicated by the lack of well preserved stratigraphic markers. However, low temperature apatite fission track (AFT) thermochronology offers important new clues by allowing the determination of exhumation histories for individual fault blocks presently exposed within the MTFC area. Previously published AFT data from crystalline basement in and near the MTFC suggest the region has a complicated pattern of exhumation. We present new AFT data from a NW-SE transect perpendicular to the principal structural grain of the MTFC. FT analyses of 15 apatite samples yielded apparent ages between 90 and 300 Ma, with mean FT length ranging from 11.8 to 13.5 μm. Thermal models based upon the age and track length data show the MTFC is comprised by multiple structural blocks with individual exhumation histories that are discrete at the 2σ confidence level. Thermal modeling of the AFT data indicates exhumation progressed from west to east, and that the final juxtaposition and exhumation of the innermost blocks took place during Cretaceous or Tertiary (possibly Neogene) time. We suggest that least some of the fracture lineaments of central Norway were re-activated during Mesozoic extension and the opening of the Norwegian sea, and may have remained active into the Cenozoic. © 2004 Elsevier Ltd. All rights reserved

Cretaceous-Tertiary palaeo-bathymetry in the northern North Sea; integration of palaeo-water depth estimates obtained by structural restoration and micropalaeontological analysis

Temporal and spatial variations in palaeo-water depth are crucial parameters in basin analysis since changes in palaeo-bathymetry detail the amount of sediment underfill during basin evolution. By carefully integrating seismic-stratigraphic observations with palaeo-water depth estimates from structural restoration and micropalaeontological data, changes in accommodation space throughout the Cretaceous-Tertiary post-rift interval are documented on a regional scale in the northern North Sea. Since it is not possible to determine the palaeo-water depth exactly, we have focussed on determining most likely water depth figures, and identifying the principal shallowing and deepening trends. The inferred trends from the investigated wells are generally in good agreement with each other on a regional scale, especially when the tectonic position within the basin is taken into account. The inferred general trends are: (1)general shallowing superimposed on several transgressive / regressive events during the Early Cretaceous; (2) deepening from the early Cenomanian to mid-Campanian; (3)shallowing from the mid-Campanian to latest Maastrichtian; (4) deepening in the Early to Late Paleocene; (5) shallowing from the Late Eocene to Late Miocene; (6) deepening from the Late Miocene to Early Pliocene; (7) shallowing during Pliocene time. The early Cenomanian to latest Maastrichtian and the late Eocene to Pliocene events correspond with changes in eustatic sea level, but the deepening / shallowing trends were probably amplified by tectono-thermal effects. The events in the Early Cretaceous, Early to Late Paleocene, and Late Miocene to Early Pliocene cannot be explained by the eustatic sea-level curve, and therefore need to be explained by purely tectono-thermal events

The influence of mechanically weak layers in controlling fault kinematics and graben configurations : Examples from analog experiments and the Norwegian continental margin

Fault systems in extensional basins commonly display geometries that vary with depth, reflecting depth- and lithology-dependent mechanical strength. Using an experimental approach, we investigate this relationship by deploying physical analog models with stratified sequences consisting of brittle–ductile (sand–silicone polymer) sequences subject to single and polyphase deformation. The experiments were used as analogs for a sandstone sequence interlayered by beds of evaporates or overpressured or unconsolidated mudstone in nature (the latter being representative of decollement horizons). Experiments (series 1 [S1]) using homogeneous and stratified quartz and feldspar sand produced asymmetric, composite single grabens with diverse fault frequencies and fault styles for the graben margin faults. For the mechanically stratified experiments with one decollement level (series 2), contrasting graben configurations were produced, in that the lowermost sequence was characterized by graben geometries of similar type to that of the S1 experiments, whereas the sequence above the decollement was characterized by large fault blocks, delineated by steepened or oversteepened faults. The experiments with two decollements (series 3) were displayed similarly but included graben geometries that widened upward, with each level being characterized by independent fault systems. The results can be used to explain strata-bound fault patterns and depth-dependent extension as seen in several places along the Norwegian continental margin and elsewhere