We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 cases, 118,538 controls) from ethnically-diverse populations. We identified five new asthma loci, uncovered two additional novel associations at two known asthma loci, established asthma associations at two loci implicated previously in comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. Enrichment of asthma risk loci in enhancer marks, especially in immune cells, suggests a major role of these loci in the regulation of immune-related mechanisms.

The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. Although little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlying mechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth and maturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P < 1.67 × 10(-8)) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased body mass index, reduced pubertal growth and earlier puberty. Whereas epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall, this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty and childhood obesity and provides new information to pinpoint processes linking these traits.

Background To date, no genome-wide association study (GWAS) has considered the combined phenotype of asthma with hay fever. Previous analyses of family data from the Tasmanian Longitudinal Health Study provide evidence that this phenotype has a stronger genetic cause than asthma without hay fever. Objective We sought to perform a GWAS of asthma with hay fever to identify variants associated with having both diseases. Methods We performed a meta-analysis of GWASs comparing persons with both physician-diagnosed asthma and hay fever (n = 6,685) with persons with neither disease (n = 14,091). Results At genome-wide significance, we identified 11 independent variants associated with the risk of having asthma with hay fever, including 2 associations reaching this level of significance with allergic disease for the first time: ZBTB10 (rs7009110; odds ratio [OR], 1.14; P = 4 × 10−9) and CLEC16A (rs62026376; OR, 1.17; P = 1 × 10−8). The rs62026376:C allele associated with increased asthma with hay fever risk has been found to be associated also with decreased expression of the nearby DEXI gene in monocytes. The 11 variants were associated with the risk of asthma and hay fever separately, but the estimated associations with the individual phenotypes were weaker than with the combined asthma with hay fever phenotype. A variant near LRRC32 was a stronger risk factor for hay fever than for asthma, whereas the reverse was observed for variants in/near GSDMA and TSLP. Single nucleotide polymorphisms with suggestive evidence for association with asthma with hay fever risk included rs41295115 near IL2RA (OR, 1.28; P = 5 × 10−7) and rs76043829 in TNS1 (OR, 1.23; P = 2 × 10−6). Conclusion By focusing on the combined phenotype of asthma with hay fever, variants associated with the risk of allergic disease can be identified with greater efficiency.

To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association (GWA) studies (N=10,768 from European ancestry enrolled in pregnancy/birth cohorts) and followed up three lead signals in six replication studies (combined N=19,089). Rs7980687 on chromosome 12q24 (P=8.1×10−9), and rs1042725 on chromosome 12q15 (P=2.8×10−10) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height1, their effects on infant head circumference were largely independent of height (P=3.8×10−7 for rs7980687, P=1.3×10−7 for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P=3.9×10−6). SNPs correlated to the 17q21 signal show genome-wide association with adult intra cranial volume2, Parkinson’s disease and other neurodegenerative diseases3-5, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.

X-linked megalocornea (MGC1) is an ocular anterior segment disorder characterized by an increased cornea diameter and deep anterior chamber evident at birth and later onset of mosaic corneal degeneration (shagreen), arcus juvenilis, and presenile cataracts. We identified copy-number variation, frameshift, missense, splice-site and nonsense mutations in the Chordin-like 1 gene (CHRDL1) on Xq23 as the cause of the condition in seven MGC1 families. CHRDL1 encodes ventroptin, a bone morphogenic protein antagonist with a proposed role in specification of topographic retinotectal projections. Electrophysiological evaluation revealed mild generalized cone system dysfunction and, in one patient, an interhemispheric asymmetry in visual evoked potentials. We show that CHRDL1 is expressed in the developing human cornea and anterior segment in addition to the retina. We explored the impact of loss of ventroptin function on brain function and morphology in vivo. CHRDL1 is differentially expressed in the human fetal brain, and there is high expression in cerebellum and neocortex. We show that MGC1 patients have a superior cognitive ability despite a striking focal loss of myelination of white matter. Our findings reveal an unexpected requirement for ventroptin during anterior segment development and the consequences of a lack of function in the retina and brain.