Linkage studies have successfully mapped loci underlying monogenic disorders, but mostly failed when applied to common diseases. Conversely, genome-wide association studies (GWASs) have identified replicable associations between thousands of SNPs and complex traits, yet capture less than half of the total heritability. In the present study we reconcile these two approaches by showing that linkage signals of height and body mass index (BMI) from 119,000 sibling pairs colocalize with GWAS-identified loci. Concordant with polygenicity, we observed the following: a genome-wide inflation of linkage test statistics; that GWAS results predict linkage signals; and that adjusting phenotypes for polygenic scores reduces linkage signals. Finally, we developed a method using recombination rate-stratified, identity-by-descent sharing between siblings to unbiasedly estimate heritability of height (0.76 +/- 0.05) and BMI (0.55 +/- 0.07). Our results imply that substantial heritability remains unaccounted for by GWAS-identified loci and this residual genetic variation is polygenic and enriched near these loci. Analyses of height and body mass index in 119,000 sibling pairs show that linkage and genome-wide association signals colocalize. Further analyses suggest that family-based linkage signals are fully consistent with a highly polygenic architecture.

Tent and Ziegler proved that the automorphism group of the Urysohn sphere is simple and that the automorphism group of the Urysohn space is simple modulo bounded automorphisms. A key component of their proof is the definition of a stationary independence relation (SIR). In this paper we prove that the existence of a SIR satisfying some extra axioms is enough to prove simplicity of the automorphism group of a countable structure. The extra axioms are chosen with applications in mind, namely homogeneous structures which admit a “metric-like amalgamation”, for example all primitive 3-constrained metrically homogeneous graphs of finite diameter from Cherlin's list.

For a complete, stable theory $T$ we construct, in a reasonably canonical way, a related stable theory $T^*$ which has higher independent amalgamation properties over the algebraic closure of the empty-set. The theory $T^*$ is an algebraic cover of $T$ and we give an explicit description of the finite covers involved in the construction of $T^*$ from $T$. This follows an approach of E. Hrushovski. If $T$ is almost strongly minimal with a $0$-definable strongly minimal set, then we show that $T^*$ has higher amalgamation over any algebraically closed subset.

Background The phenotypic overlap between Autism Spectrum Disorders (ASD) and schizophrenia is complex and dates back to Kanner in 1943, including symptomatic similarities such as social withdrawal, communication impairment, and poor eye contact. Recent theories proposed a “continuum of psychosis”, despite differences between disorders, based on shared genetic susceptibility among psychiatric conditions and genetic overlap with milder symptoms in unaffected individuals from the general population. Symptoms of ASD however typically occur during early childhood, whereas the first signs of schizophrenia appear during adolescence and early adulthood. Thus, genetic links with population-based traits may also follow a developmental pattern. Our study was conducted to investigate genetic relationships between social-communication difficulties during childhood and adolescence and both common variation in clinical ASD and schizophrenia.

In this paper, we investigate the connection between infinite permutation monoids and bimorphism monoids of first-order structures. Taking our lead from the study of automorphism groups of structures as infinite permutation groups and the more recent developments in the field of homomorphism-homogeneous structures, we establish a series of results that underline this connection. Of particular interest is the idea of MB-homogeneity; a relational structure M is MB-homogeneous if every monomorphism between finite substructures ofM extends to a bimorphism ofM. The results in question include a characterisation of closed permutation monoids, a Fräıssé-like theorem for MB-homogeneous structures, and the construction of 20 pairwise non-isomorphic countable MB-homogeneous graphs. We prove that any finite group arises as the automorphism group of some MB-homogeneous graph and use this to construct oligomorphic permutation monoids with any given finite group of units. We also consider MB-homogeneity for various well-known examples of homogeneous structures and in particular give a complete classification of countable homogeneous undirected graphs that are also MB-homogeneous.

Peer behaviour plays an important role in the development of social adjustment, though little is known about its genetic architecture. We conducted a twin study combined with a genome-wide complex trait analysis (GCTA) and a genome-wide screen to characterise genetic influences on problematic peer behaviour during childhood and adolescence. This included a series of longitudinal measures (parent-reported Strengths-and-Difficulties Questionnaire) from a UK population-based birth-cohort (ALSPAC, 4–17 years), and a UK twin sample (TEDS, 4–11 years). Longitudinal twin analysis (TEDS; N ≤ 7,366 twin pairs) showed that peer problems in childhood are heritable (4–11 years, 0.60 < twin- h 2 ≤ 0.71) but genetically heterogeneous from age to age (4–11 years, twin- r g = 0.30). GCTA (ALSPAC: N ≤ 5,608, TEDS: N ≤ 2,691) provided furthermore little support for the contribution of measured common genetic variants during childhood (4–12 years, 0.02 < GCTA- h 2 (Meta) ≤ 0.11) though these influences become stronger in adolescence (13–17 years, 0.14 < GCTA- h 2 (ALSPAC) ≤ 0.27). A subsequent cross-sectional genome-wide screen in ALSPAC ( N ≤ 6,000) focussed on peer problems with the highest GCTA-heritability (10, 13 and 17 years, 0.0002 < GCTA- P ≤ 0.03). Single variant signals ( P ≤ 10 −5 ) were followed up in TEDS ( N ≤ 2835, 9 and 11 years) and, in search for autism quantitative trait loci, explored within two autism samples (AGRE: N Pedigrees = 793; ACC: N Cases = 1,453/ N Controls = 7,070). There was, however, no evidence for association in TEDS and little evidence for an overlap with the autistic continuum. In summary, our findings suggest that problematic peer relationships are heritable but genetically complex and heterogeneous from age to age, with an increase in common measurable genetic variation during adolescence.

We show that if $G$ is a non-archimedean, Roelcke precompact, Polish group, then $G$ has Kazhdan's property (T). Moreover, if $G$ has a smallest open subgroup of finite index, then $G$ has a finite Kazhdan set. Examples of such $G$ include automorphism groups of countable $\omega$-categorical structures, that is, the closed, oligomorphic permutation groups on a countable set. The proof uses work of the second author on the unitary representations of such groups, together with a separation result for infinite permutation groups. The latter allows the construction of a non-abelian free subgroup of $G$ acting freely in all infinite transitive permutation representations of $G$.

We show that the automorphism groups of certain countable structures obtained using the Hrushovski amalgamation method are simple groups. The structures we consider are the 'uncollapsed' structures of infinite Morley rank obtained by the ab initio construction and the (unstable) omega-categorical pseudoplanes. The simplicity of the automorphism groups of these follows from results which generalize work of Lascar and of Tent and Ziegler.

ObjectiveTo use high‐density genotyping to investigate the genetic associations of acute anterior uveitis (AAU) in patients with and those without ankylosing spondylitis (AS).MethodsWe genotyped samples from 1,711 patients with AAU (either primary or combined with AS), 2,339 AS patients without AAU, and 10,000 control subjects on an Illumina Immunochip Infinium microarray. We also used data for AS patients from previous genome‐wide association studies to investigate the AS risk locus ANTXR2 for its putative effect in AAU. ANTXR2 expression in mouse eyes was investigated by real‐time quantitative reverse transcription–polymerase chain reaction.ResultsA comparison between all patients with AAU and healthy control subjects showed strong association over HLA–B, corresponding to the HLA–B27 tag single‐nucleotide polymorphism rs116488202. The association of 3 non–major histocompatibility complex loci, IL23R, the intergenic region 2p15, and ERAP1, reached genome‐wide significance (P < 5 × 10−8). Five loci harboring the immune‐related genes IL10–IL19, IL18R1–IL1R1, IL6R, the chromosome 1q32 locus harboring KIF21B, as well as the eye‐related gene EYS, were also associated, reaching a suggestive level of significance (P < 5 × 10−6). Several previously confirmed AS associations demonstrated significant differences in effect size between AS patients with AAU and AS patients without AAU. ANTXR2 expression varied across eye compartments.ConclusionThese findings of both novel AAU‐specific associations and associations shared with AS demonstrate overlapping but also distinct genetic susceptibility loci for AAU and AS. The associations in IL10 and IL18R1 are shared with inflammatory bowel disease, suggesting common etiologic pathways.

Abstract Background: Ecological and epidemiological studies have identified an inverse association of intensity and duration of sunlight exposure with prostate cancer, which may be explained by a reduction in vitamin D synthesis. Pigmentation traits influence sun exposure and therefore may affect prostate cancer risk. Because observational studies are vulnerable to confounding and measurement error, we used Mendelian randomization to examine the relationship of sun exposure with both prostate cancer risk and the intermediate phenotype, plasma levels of vitamin D. Methods: We created a tanning, a skin color, and a freckling score as combinations of single nucleotide polymorphisms that have been previously associated with these phenotypes. A higher score indicates propensity to burn, have a lighter skin color and freckles. The scores were tested for association with vitamin D levels (25-hydroxyvitamin-D and 1,25-dihydroxyvitamin-D) and prostate-specific antigen detected prostate cancer in 3,123 White British individuals enrolled in the Prostate Testing for cancer and Treatment (ProtecT) study. Results: The freckling score was inversely associated with 25(OH)D levels [change in 25(OH)D per score unit −0.27; 95% CI, −0.52% to −0.01%], and the tanning score was positively associated with prostate cancer risk (OR = 1.05; 95% CI, 1.02–1.09), after adjustment for population stratification and potential confounders. Conclusions: Individuals who tend to burn are more likely to spend less time in the sun and consequently have lower plasma vitamin D levels and higher susceptibility to prostate cancer. Impact: The use of pigmentation-related genetic scores is valuable for the assessment of the potential benefits of sun exposure with respect to prostate cancer risk. Cancer Epidemiol Biomarkers Prev; 22(4); 597–606. ©2013 AACR.

Twin and family studies indicate that the timing of primary tooth eruption is highly heritable, with estimates typically exceeding 80%. To identify variants involved in primary tooth eruption, we performed a population-based genome-wide association study of 'age at first tooth' and 'number of teeth' using 5998 and 6609 individuals, respectively, from the Avon Longitudinal Study of Parents and Children (ALSPAC) and 5403 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966). We tested 2 446 724 SNPs imputed in both studies. Analyses were controlled for the effect of gestational age, sex and age of measurement. Results from the two studies were combined using fixed effects inverse variance meta-analysis. We identified a total of 15 independent loci, with 10 loci reaching genome-wide significance (P < 5 × 10−8) for 'age at first tooth' and 11 loci for 'number of teeth'. Together, these associations explain 6.06% of the variation in 'age of first tooth' and 4.76% of the variation in 'number of teeth'. The identified loci included eight previously unidentified loci, some containing genes known to play a role in tooth and other developmental pathways, including an SNP in the protein-coding region of BMP4 (rs17563, P = 9.080 × 10−17). Three of these loci, containing the genes HMGA2, AJUBA and ADK, also showed evidence of association with craniofacial distances, particularly those indexing facial width. Our results suggest that the genome-wide association approach is a powerful strategy for detecting variants involved in tooth eruption, and potentially craniofacial growth and more generally organ development.

Obesity is an established risk factor for type 2 diabetes (T2D) and they are metabolically related through the mechanism of insulin resistance. In order to explore how common genetic variants associated with T2D correlate with body mass index (BMI), we examined the influence of 25 T2D associated loci on obesity risk. We used 5056 individuals (2528 sib-pairs) recruited in Indian Migration Study and conducted within sib-pair analysis for six obesity phenotypes. We found associations of variants in CXCR4 (rs932206) and HHEX (rs5015480) with higher body mass index (BMI) (β=0.13, p=0.001) and (β=0.09, p=0.002), respectively and weight (β=0.13, p=0.001) and (β=0.09, p=0.001), respectively. CXCR4 variant was also strongly associated with body fat (β=0.10, p=0.0004). In addition, we demonstrated associations of CXCR4 and HHEX with overweight/obesity (OR=1.6, p=0.003) and (OR=1.4, p=0.002), respectively, in 1333 sib-pairs (2666 individuals). We observed marginal evidence of associations between variants at six loci (TCF7L2, NGN3, FOXA2, LOC646279, FLJ39370 and THADA) and waist hip ratio (WHR), BMI and/or overweight which needs to be validated in larger set of samples. All the above findings were independent of daily energy consumption and physical activity level. The risk score estimates based on eight significant loci (including nominal associations) showed associations with WHR and body fat which were independent of BMI. In summary, we establish the role of T2D associated loci in influencing the measures of obesity in Indian population, suggesting common underlying pathophysiology across populations.

This paper explores the movements and placings that work to configure food as waste. At issue here—following the work of Nicky Gregson, Kevin Hetherington, and Rolland Munro—are the multiple conduits that exist for ‘moving things along’ and the idea that consumption research needs to move beyond the unfortunate conjunction of disposal and waste. I suggest that the disposal of surplus food is enacted via a graduated process in which it first enters a ‘gap’ where ambiguities and anxieties surrounding its residual value and onward trajectory are addressed. Drawing on ethnographic examples, I explore the shifting contours and gradients that reduce the possibilities for disposing of food through conduits in which it can be handed down, handed around, or otherwise saved from wastage. I also unpack the overwhelming tendency for surplus food to be cast as ‘excess’ and placed in conduits—typically the bin—that connect it to the waste stream. Crucially, it is suggested that food is a specific genre of material culture and that this underpins the normativity of its binning alongside the attendant prevention of its recirculation or recovery. To conclude, I reflect on the broader implications of this analysis for understandings of consumption, disposal, and waste.

We investigate the isomorphism types of combinatorial geometries arising from Hrushovski's flat strongly minimal structures and answer some questions from Hrushovski's original paper.

An intermediate stage in Hrushovski's construction of flat strongly minimal structures in a relational language L produces omega-stable structures of rank omega. We analyze the pregeometries given by forking on the regular type of rank omega in these structures. We show that varying L can affect the (local) isomorphism type of the pregeometry, but not its finite subpregeometries. A sequel will compare these to the pregeometries of the strongly minimal structures.

We give an exposition of some results from matroid theory which characterise the finite pregeometries arising from Hrushovski's predimension construction. As a corollary, we observe that a finite pregeometry which satisfies Hrushovski's flatness condition arises from a predimension.