Single nucleotide polymorphisms (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 by simulations based upon 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 (LD) between causal variants and genotyped SNPs, exacerbated by causal variants having lower minor allele frequency (MAF) than the SNPs explored to date.

Human skin pigmentation shows a strong positive correlation with ultraviolet radiation intensity, suggesting that variation in skin color is, at least partially, due to adaptation via natural selection. We investigated the evolution of pigmentation variation by testing for the presence of positive directional selection in 6 pigmentation genes using an empirical F(ST) approach, through an examination of global diversity patterns of these genes in the Centre d'Etude du Polymorphisme Humain (CEPH)-Diversity Panel, and by exploring signatures of selection in data from the International HapMap project. Additionally, we demonstrated a role for MATP in determining normal skin pigmentation variation using admixture mapping methods. Taken together (with the results of previous admixture mapping studies), these results point to the importance of several genes in shaping the pigmentation phenotype and a complex evolutionary history involving strong selection. Polymorphisms in 2 genes, ASIP and OCA2, may play a shared role in shaping light and dark pigmentation across the globe, whereas SLC24A5, MATP, and TYR have a predominant role in the evolution of light skin in Europeans but not in East Asians. These findings support a case for the recent convergent evolution of a lighter pigmentation phenotype in Europeans and East Asians.

Major depressive disorder (MDD) is a common complex disorder with a partly genetic etiology. We conducted a genome-wide association study of the MDD2000+ sample (2431 cases, 3673 screened controls and >1 M imputed single-nucleotide polymorphisms (SNPs)). No SNPs achieved genome-wide significance either in the MDD2000+ study, or in meta-analysis with two other studies totaling 5763 cases and 6901 controls. These results imply that common variants of intermediate or large effect do not have main effects in the genetic architecture of MDD. Suggestive but notable results were (a) gene-based tests suggesting roles for adenylate cyclase 3 (ADCY3, 2p23.3) and galanin (GAL, 11q13.3); published functional evidence relates both of these to MDD and serotonergic signaling; (b) support for the bipolar disorder risk variant SNP rs1006737 in CACNA1C (P=0.020, odds ratio=1.10); and (c) lack of support for rs2251219, a SNP identified in a meta-analysis of affective disorder studies (P=0.51). We estimate that sample sizes 1.8- to 2.4-fold greater are needed for association studies of MDD compared with those for schizophrenia to detect variants that explain the same proportion of total variance in liability. Larger study cohorts characterized for genetic and environmental risk factors accumulated prospectively are likely to be needed to dissect more fully the etiology of MDD.

We report a genome-wide association study to iron status. We identify an association of SNPs in TPMRSS6 to serum iron (rs855791, combined P = 1.5×10−20), transferrin saturation (combined P = 2.2×10−23), and erythrocyte mean cell volume (MCV, combined P = 1.1×10−10). We also find suggestive evidence of association with blood haemoglobin levels (combined P = 5.3×10−7). These findings demonstrate the involvement of TMPRSS6 in control of iron homeostasis and in normal erythropoiesis.

Hair morphology is highly differentiated between populations and among people of European ancestry. Whereas hair morphology in East Asian populations has been studied extensively, relatively little is known about the genetics of this trait in Europeans. We performed a genome-wide association scan for hair morphology (straight, wavy, curly) in three Australian samples of European descent. All three samples showed evidence of association implicating the Trichohyalin gene (TCHH), which is expressed in the developing inner root sheath of the hair follicle, and explaining approximately 6% of variance (p=1.5x10(-31)). These variants are at their highest frequency in Northern Europeans, paralleling the distribution of the straight-hair EDAR variant in Asian populations.

Human facial diversity is substantial, complex, and largely scientifically unexplained. We used spatially dense quasi-landmarks to measure face shape in population samples with mixed West African and European ancestry from three locations (United States, Brazil, and Cape Verde). Using bootstrapped response-based imputation modeling (BRIM), we uncover the relationships between facial variation and the effects of sex, genomic ancestry, and a subset of craniofacial candidate genes. The facial effects of these variables are summarized as response-based imputed predictor (RIP) variables, which are validated using self-reported sex, genomic ancestry, and observer-based facial ratings (femininity and proportional ancestry) and judgments (sex and population group). By jointly modeling sex, genomic ancestry, and genotype, the independent effects of particular alleles on facial features can be uncovered. Results on a set of 20 genes showing significant effects on facial features provide support for this approach as a novel means to identify genes affecting normal-range facial features and for approximating the appearance of a face from genetic markers.

Genetic and fossil evidence supports a single, recent (<200,000 yr) origin of modern Homo sapiens in Africa, followed by later population divergence and dispersal across the globe (the ''Out of Africa'' model). However, there is less agreement on the exact nature of this migration event and dispersal of populations relative to one another. We use the empirically observed genetic correlation structure (or linkage disequilibrium) between 242,000 genome-wide single nucleotide polymorphisms (SNPs) in 17 global populations to reconstruct two key parameters of human evolution: effective population size (N e ) and population divergence times (T). A linkage disequilibrium (LD)-based approach allows changes in human population size to be traced over time and reveals a substantial reduction in N e accompanying the ''Out of Africa'' exodus as well as the dramatic re-expansion of non-Africans as they spread across the globe. Secondly, two parallel estimates of population divergence times provide clear evidence of population dispersal patterns ''Out of Africa'' and subsequent dispersal of proto-European and proto-East Asian populations. Estimates of divergence times between European-African and East Asian-African populations are inconsistent with its simplest manifestation: a single dispersal from the continent followed by a split into Western and Eastern Eurasian branches. Rather, population divergence times are consistent with substantial ancient gene flow to the proto-European population after its divergence with proto-East Asians, suggesting distinct, early dispersals of modern H. sapiens from Africa. We use simulated genetic polymorphism data to demonstrate the validity of our conclusions against alternative population demographic scenarios.

Background Given moderately strong genetic contributions to variation in alcoholism and heaviness of drinking (50–60% heritability), with high correlation of genetic influences, we have conducted a quantitative trait genomewide association study for phenotypes related to alcohol use and dependence. Methods Diagnostic interview and blood/buccal samples were obtained from sibships ascertained through the Australian Twin Registry. Genomewide SNP genotyping was performed with 8754 individuals [2062 alcohol dependent cases] selected for informativeness for alcohol use disorder and associated quantitative traits. Family-based association tests were performed for alcohol dependence, dependence factor score and heaviness of drinking factor score, with confirmatory case-population control comparisons using an unassessed population control series of 3393 Australians with genomewide SNP data. Results No findings reached genomewide significance (p=8.4×10−8 for this study), with lowest p-value for primary phenotypes of 1.2×10−7. Convergent findings for quantitative consumption and diagnostic and quantitative dependence measures suggest possible roles for a transmembrane protein gene (TMEM108) and for ANKS1A. The major finding, however, was small effect sizes estimated for individual SNPs, suggesting that hundreds of genetic variants make modest contributions (1/4% of variance or less) to alcohol dependence risk. Conclusions We conclude that (i) meta-analyses of consumption data may contribute usefully to gene-discovery; (ii) translation of human alcoholism GWAS results to drug discovery or clinically useful prediction of risk will be challenging; (iii) through accumulation across studies, GWAS data may become valuable for improved genetic risk differentiation in research in biological psychiatry (e.g. prospective high-risk or resilience studies).