Common SNPs explain a large proportion of the heritability for human height

SNPs discovered by genome-wide association studies (GWASs) account for only a small fraction of the genetic variation of complex traits in human populations. Where is the remaining heritability? We estimated the proportion of variance for human height explained by 294,831 SNPs genotyped on 3,925 unrelated individuals using a linear model analysis, and validated the estimation method with simulations based on the observed genotype data. We show that 45% of variance can be explained by considering all SNPs simultaneously. Thus, most of the heritability is not missing but has not previously been detected because the individual effects are too small to pass stringent significance tests. We provide evidence that the remaining heritability is due to incomplete linkage disequilibrium between causal variants and genotyped SNPs, exacerbated by causal variants having lower minor allele frequency than the SNPs explored to date.

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Rotary veneering of plantation-grown spotted gum (Corymbia citriodora subsp. variegata) and Dunn's white gum (Eucalyptus dunnii)

This report evaluates the wood and veneer properties of plantation-grown spotted gum (Corymbia citriodora subsp. variegata, or CCV) and Dunn's white gum (Eucalyptus dunnii), grown at different stockings, in thinning trials near Ellangowan in north-east New South Wales (mean annual rainfall 1050 mm) and Kingaroy in south-east Queensland (mean annual rainfall 873 mm). Thinning trials were established at age seven years. Both species showed a significant increase in stem diameter growth of the dominant trees in response to thinning. At age 10 years, trees from the unthinned (950–1270 stems ha-1) and 300 stems ha-1 treatments were selected for veneering. Five dominant trees were felled from each combination of species x sites x thinning treatment. Diameter at breast height over bark of the selected trees ranged from 20 cm to 27 cm at Ellangowan, and 19 cm to 26 cm at Kingaroy. From each tree, 1.5 m long billets were removed at two positions: a butt billet from 0.3–1.8 m above ground and a top billet from approximately 5.5–7.0 m. Log end splitting was assessed 24 hours after harvesting and again after steaming, approximately four days after harvesting. Disks from just above both billets were collected for assessment of wood properties. Billets were peeled on a spindleless veneer lathe to produce a full veneer ribbon with a target green thickness of 2.8 to 3.0 mm. The 1.55 m wide (tangential dimension) veneer sheets were dried and graded according to AS/NZ Standard 2269:2008, which describes four veneer grades. Veneer samples taken along the length of the veneer ribbon, at regular intervals of 1.55 m, were tested for stiffness, shrinkage and density. Veneer length measurements were used to calculate the radial distance of each sample from the central axis of the billet. Overall veneer gross recoveries ranged from 50% to 70%. They were significantly lower at the Kingaroy site, for both species. The veneer recoveries achieved were 2–3 times higher than typical green off saw recoveries from small plantation hardwood logs of similar diameter. Most of the veneer recovered was classified as D-grade. CCV trees from the Ellangowan site yielded up to 38% of the better C-grade and higher grade veneers. The main limiting factors that prevented veneer from meeting higher grades were the presence of kino defects and encased knots. Splits in E. dunnii veneer also contributed to reduced grade quality. Log end splits were higher for E. dunnii than for CCV, and logs from Ellangowan exhibited more severe splitting. Split index was generally higher for top than for butt billets. Split index was strongly correlated with the average veneer grade from corresponding billets. The Ellangowan site, where rainfall was higher and trees grew faster, yielded significantly denser and stiffer veneers than did the drier sites near Kingaroy, where tree growth was slower. The difference was more pronounced for E. dunnii than for CCV. Differences in measured wood properties between thinned and unthinned treatments were generally small and not significant. On average, 10% of billet volume was lost during the peeling rounding-up process. Much of the wood laid down following thinning was removed during rounding-up, meaning the effect of thinning on veneer properties could not be effectively assessed. CCV was confirmed as having high veneer density and very good veneer stiffness, exceeding 15 GPa, making it very suitable for structural products. E. dunnii also demonstrated good potential as a useful structural plywood resource, achieving stiffness above 10 GPa. Veneer stiffness and density in CCV increased from pith to bark at both sites, while for E. dunnii there was a radial increase in these properties at the Ellangowan site only. At the drier Kingaroy site, veneer stiffness and density declined from mid-radius to the log periphery. This may be associated with prolonged drought from 2005 to 2009, corresponding to the later years of tree growth at the Kingaroy site. CCV appeared to be less sensitive to drought conditions. Standing tree acoustic velocity, determined by the Fakopp time-of-flight method, provided a reliable prediction of average veneer stiffness for both species (R2=0.78 for CCV and R2=0.90 for E. dunnii) suggesting that the Fakopp method may be a useful indicator of tree and stand quality, in terms of veneer stiffness in standing trees.

Within-family outliers: Segregating alleles or environmental effects? A linkage analysis of height from 5815 sibling pairs

Most information in linkage analysis for quantitative traits comes from pairs of relatives that are phenotypically most discordant or concordant. Confounding this, within-family outliers from non-genetic causes may create false positives and negatives. We investigated the influence of within-family outliers empirically, using one of the largest genome-wide linkage scans for height. The subjects were drawn from Australian twin cohorts consisting of 8447 individuals in 2861 families, providing a total of 5815 possible pairs of siblings in sibships. A variance component linkage analysis was performed, either including or excluding the within-family outliers. Using the entire dataset, the largest LOD scores were on chromosome 15q (LOD 2.3) and 11q (1.5). Excluding within-family outliers increased the LOD score for most regions, but the LOD score on chromosome 15 decreased from 2.3 to 1.2, suggesting that the outliers may create false negatives and false positives, although rare alleles of large effect may also be an explanation. Several regions suggestive of linkage to height were found after removing the outliers, including 1q23.1 (2.0), 3q22.1 (1.9) and 5q32 (2.3). We conclude that the investigation of the effect of within-family outliers, which is usually neglected, should be a standard quality control measure in linkage analysis for complex traits and may reduce the noise for the search of common variants of modest effect size as well as help identify rare variants of large effect and clinical significance. We suggest that the effect of within-family outliers deserves further investigation via theoretical and simulation studies.

The effect of temperature on height growth of Scots pine in northern Finland

The effect of temperature on height growth of Scots pine in the northern boreal zone in Lapland was studied in two different time scales. Intra-annual growth was monitored in four stands in up to four growing seasons using an approximately biweekly measurement interval. Inter-annual growth was studied using growth records representing seven stands and five geographical locations. All the stands were growing on a dry to semi-dry heath that is a typical site type for pine stands in Finland. The applied methodology is based on applied time-series analysis and multilevel modelling. Intra-annual elongation of the leader shoot correlated with temperature sum accumulation. Height growth ceased when, on average, 41% of the relative temperature sum of the site was achieved (observed minimum and maximum were 38% and 43%). The relative temperature sum was calculated by dividing the actual temperature sum by the long-term mean of the total annual temperature sum for the site. Our results suggest that annual height growth ceases when a location-specific temperature sum threshold is attained. The positive effect of the mean July temperature of the previous year on annual height increment proved to be very strong at high latitudes. The mean November temperature of the year before the previous had a statistically significantly effect on height increment in the three northernmost stands. The effect of mean monthly precipitation on annual height growth was statistically insignificant. There was a non-linear dependence between length and needle density of annual shoots. Exceptionally low height growth results in high needle-density, but the effect is weaker in years of average or good height growth. Radial growth and next year s height growth are both largely controlled by current July temperature. Nevertheless, their growth variation in terms of minimum and maximum is not necessarily strongly correlated. This is partly because height growth is more sensitive to changes in temperature. In addition, the actual effective temperature period is not exactly the same for these two growth components. Yet, there is a long-term balance that was also statistically distinguishable; radial growth correlated significantly with height growth with a lag of 2 years. Temperature periods shorter than a month are more effective variables than mean monthly values, but the improvement is on the scale of modest to good when applying Julian days or growing-degree-days as pointers.

A Microprocessor-Based Pulse-Height Analyzer

Need to analyze particles in a flow? This system takes electrical pulses from acoustical or optical sensors and groups them into bands representing ranges of particle sizes.

Liveweight prediction from hip height, condition score, fetal age and breed in tropical female cattle

Hip height, body condition, subcutaneous fat, eye muscle area, percentage Bos taurus, fetal age and diet digestibility data were collected at 17 372 assessments on 2181 Brahman and tropical composite (average 28% Brahman) female cattle aged between 0.5 and 7.5 years of age at five sites across Queensland. The study validated the subtraction of previously published estimates of gravid uterine weight to correct liveweight to the non-pregnant status. Hip height and liveweight were linearly related (Brahman: P<0.001, R-2 = 58%; tropical composite P<0.001, R-2 = 67%). Liveweight varied by 12-14% per body condition score (5-point scale) as cows differed from moderate condition (P<0.01). Parallel effects were also found due to subcutaneous rump fat depth and eye muscle area, which were highly correlated with each other and body condition score (r = 0.7-0.8). Liveweight differed from average by 1.65-1.66% per mm of rump fat depth and 0.71-0.76% per cm(2) of eye muscle area (P<0.01). Estimated dry matter digestibility of pasture consumed had no consistent effect in predicting liveweight and was therefore excluded from final models. A method developed to estimate full liveweight of post-weaning age female beef cattle from the other measures taken predicted liveweight to within 10 and 23% of that recorded for 65 and 95% of cases, respectively. For a 95% chance of predicted group average liveweight (body condition score used) being within 5, 4, 3, 2 and 1% of actual group average liveweight required 23, 36, 62, 137 and 521 females, respectively, if precision and accuracy of measurements matches that used in the research. Non-pregnant Bos taurus female cattle were calculated to be 10-40% heavier than Brahmans at the same hip height and body condition, indicating a substantial conformational difference. The liveweight prediction method was applied to a validation population of 83 unrelated groups of cattle weighed in extensive commercial situations on 119 days over 18 months (20 917 assessments). Liveweight prediction in the validation population exceeded average recorded liveweight for weigh groups by an average of 19 kg (similar to 6%) demonstrating the difficulty of achieving accurate and precise animal measurements under extensive commercial grazing conditions.

Lens shape and refractive index distribution in type 1 diabetes

Purpose: To compare lens dimensions and refractive index distributions in type 1 diabetes and age-matched control groups. Methods: There were 17 participants with type 1 diabetes, consisting of two subgroups (7 young [23 ± 4 years] and 10 older [54 ± 4 years] participants), with 23 controls (13 young, 24 ± 4 years; 10 older, 55 ± 4 years). For each participant, one eye was tested with relaxed accommodation. A 3T clinical magnetic resonance imaging scanner was used to image the eye, employing a multiple spin echo (MSE) sequence to determine lens dimensions and refractive index profiles along the equatorial and axial directions. Results: The diabetes group had significantly smaller lens equatorial diameters and larger lens axial thicknesses than the control group (diameter mean ± 95% confidence interval [CI]: diabetes group 8.65 ± 0.26 mm, control group 9.42 ± 0.18 mm; axial thickness: diabetes group 4.33 ± 0.30 mm, control group 3.80 ± 0.14 mm). These differences were also significant within each age group. The older group had significantly greater axial thickness than the young group (older group 4.35 ± 0.26 mm, young group 3.70 ± 0.25 mm). Center refractive indices of diabetes and control groups were not significantly different. There were some statistically significant differences between the refractive index fitting parameters of young and older groups, but not between diabetes and control groups of the same age. Conclusions: Smaller lens diameters occurred in the diabetes groups than in the age-matched control groups. Differences in refractive index distribution between persons with and without diabetes are too small to have important effects on instruments measuring axial thickness.

Editorial: Measuring refractive index distribution in the human eye lens

Non-invasive measurements of the age dependence of refractive index distribution in human eye lenses in vitro using a novel X-ray Talbot Interferometry method. In their paper, the authors make frequent reference to our own work in which we employed magnetic resonance imaging (MRI) to make similar non-invasive measurements of the refractive index distribution in the human eye lens [2, 3]. Prior to the current work, ours was the only method for making such measurements both non-invasively and without prior assumptions about the shape of the refractive index distribution. For this reason, the latest work is to be welcomed. However at several points in the paper, Pierscionek et al. [1] make statements about our technique which are factually incorrect...

Do small-aperture presbyopic corrections influence the visual field?

Purpose To explore the effect of small-aperture optics, designed to aid presbyopes by increasing ocular depth-of-focus, on measurements of the visual field. Methods Simple theoretical and ray-tracing models were used to predict the impact of different designs of small-aperture contact lenses or corneal inlays on the proportion of light passing through natural pupils of various diameters as a function of the direction in the visual field. The left eyes of five healthy volunteers were tested using three afocal, hand-painted opaque soft contact lenses (www.davidthomas.com). Two were opaque over a 10 mm diameter but had central clear circular apertures of 1.5 and 3.0 mm in diameter. The third had an annular opaque zone with inner and outer diameters of 1.5 and 4.0 mm, approximately simulating the geometry of the KAMRA inlay (www.acufocus.com). A fourth, clear lens was used for comparison purposes. Visual fields along the horizontal meridian were evaluated up to 50° eccentricity with static automated perimetry (Medmont M700, stimulus Goldmann-size III; www.medmont.com). Results According to ray-tracing, the two lenses with the circular apertures were expected to reduce the relative transmittance of the pupil to zero at specific field angles (around 60° for the conditions of the experimental measurements). In contrast, the annular stop had no effect on the absolute field but relative transmittance was reduced over the central area of the field, the exact effects depending upon the natural pupil diameter. Experimental results broadly agreed with these theoretical expectations. With the 1.5 and 3.0 mm pupils, only minor losses in sensitivity (around 2 dB) in comparison with the clear-lens case occurred across the central 10° radius of field. Beyond this angle, sensitivity losses increased, to reach about 7 dB at the edge of the measured field (50°). The field results with the annular stop showed at most only a slight loss in sensitivity (≤3 dB) across the measured field. Conclusion The present theoretical and experimental results support earlier clinical findings that KAMRA-type annular stops, unlike circular artificial pupils, have only minor effects on measurements of the visual field.

Effects of seed origin latitude on the timing of height growth cessation and field performance of silver birch

The aim of this thesis was to increase our knowledge about the effects of seed origin on the timing of height growth cessation and field performance of silver birch from different latitudes, with special attention paid to the browsing damage by moose in young birch plantations. The effect of seed origin latitude and sowing time on timing of height growth cessation of first-year seedlings was studied in a greenhouse experiment with seven seed origins (lat. 58º - 67ºN). Variation in critical night length (CNL) for 50 % bud set within two latitudinally distant stands (60º and 67ºN) was studied in three phytotron experiments. Browsing by moose on 5-11 -year-old silver birch saplings from latitudinally different seed origins (53º - 67ºN) was studied in a field experiment in southern Finland. Yield and stem quality of 22-year-old silver birch trees of Baltic, Finnish and Russian origin (54º - 63ºN) and the effect of latitudinal seed transfers were studied in two provenance trials at Tuusula, southern and Viitasaari, central Finland. The timing of height growth cessation depended systematically on latitude of seed origin and sowing date. The more northern the seed origin, the earlier the growth cessation and the shorter the growth period. Later sowing dates delayed growth cessation but also shortened the growth period. The mean CNL of the southern ecotype was longer, 6.3 ± 0.2 h (95 % confidence interval), than that of the northern ecotype, 3.1 ± 0.3 h. Within-ecotype variance of the CNL was higher in the northern ecotype (0.484 h2) than in the southern ecotype (0.150 h2). Browsing by moose decreased with increasing latitude of seed origin and sapling height. Origins transferred from more southern latitudes were more heavily browsed than the more northern native ones. Southern Finnish seed origins produced the highest volume per unit area in central Finland (lat. 63º11'N). Estonian and north Latvian stand seed origins, and the southern Finnish plus tree origins, were the most productive ones in southern Finland (lat. 60º21'N). Latitudinal seed transfer distance had a significant effect on survival, stem volume/ha and proportion of trees with a stem defect. The relationship of both survival and stem volume/ha to the latitudinal seed transfer distance was curvilinear. Volume was increased by transferring seed from ca. 2 degrees of latitude from the south. A longer transfer from the south, and transfer from the north, decreased the yield. The proportion of trees with a stem defect increased linearly in relation to the latitudinal seed transfer distance from the south.

View of Heidelberg from "Philosophenhoehe" (Philosopher's Height) Cities, Towns, and Villages

Handwritten information on back of photo(s).

Multi-trait assessment of early-in-life female, male and genomic measures for use in genetic selection to improve female reproductive performance of Brahman cattle

Early-in-life female and male measures with potential to be practical genetic indicators were chosen from earlier analyses and examined together with genomic measures for multi-trait use to improve female reproduction of Brahman cattle. Combinations of measures were evaluated on the genetic gains expected from selection of sires and dams for each of age at puberty (AGECL, i.e. first observation of a corpus luteum), lactation anoestrous interval in 3-year-old cows (LAI), and lifetime annual weaning rate (LAWR, i.e. the weaning rate of cows based on the number of annual matings they experienced over six possible matings). Selection was on an index of comparable records for each combination. Selection intensities were less than theoretically possible but assumed a concerted selection effort was able to be made across the Brahman breed. The results suggested that substantial genetic gains could be possible but need to be confirmed in other data. The estimated increase in LAWR in 10 years, for combinations without or with genomic measures, ranged from 8 to 12 calves weaned per 100 cows from selection of sires, and from 12 to 15 calves weaned per 100 cows from selection of sires and dams. Corresponding reductions in LAI were 60-103 days or 94-136 days, and those for AGECL were 95-125 or 141-176 days, respectively. Coat score (a measure of the sleekness or wooliness of the coat) and hip height in females, and preputial eversion and liveweight in males, were measures that may warrant wider recording for Brahman female reproduction genetic evaluation. Pregnancy-test outcomes from Matings 1 and 2 also should be recorded. Percentage normal sperm may be important to record for reducing LAI and scrotal size and serum insulin-like growth factor-I concentration in heifers at 18 months for reducing AGECL. Use of a genomic estimated breeding value (EBV) in combination with other measures added to genetic gains, especially at genomic EBV accuracies of 40%. Accuracies of genomic EBVs needed to approach 60% for the genomic EBV to be the most important contributor to gains in the combinations of measures studied.