Human genetic diversity in the Pacific has not been adequately sampled, particularly in Melanesia. As a result, population relationships there have been open to debate. A genome scan of autosomal markers (687 microsatellites and 203 insertions/deletions) on 952 individuals from 41 Pacific populations now provides the basis for understanding the remarkable nature of Melanesian variation, and for a more accurate comparison of these Pacific populations with previously studied groups from other regions. It also shows how textured human population variation can be in particular circumstances. Genetic diversity within individual Pacific populations is shown to be very low, while differentiation among Melanesian groups is high. Melanesian differentiation varies not only between islands, but also by island size and topographical complexity. The greatest distinctions are among the isolated groups in large island interiors, which are also the most internally homogeneous. The pattern loosely tracks language distinctions. Papuan-speaking groups are the most differentiated, and Austronesian or Oceanic-speaking groups, which tend to live along the coastlines, are more intermixed. A small “Austronesian” genetic signature (always <20%) was detected in less than half the Melanesian groups that speak Austronesian languages, and is entirely lacking in Papuan-speaking groups. Although the Polynesians are also distinctive, they tend to cluster with Micronesians, Taiwan Aborigines, and East Asians, and not Melanesians. These findings contribute to a resolution to the debates over Polynesian origins and their past interactions with Melanesians. With regard to genetics, the earlier studies had heavily relied on the evidence from single locus mitochondrial DNA or Y chromosome variation. Neither of these provided an unequivocal signal of phylogenetic relations or population intermixture proportions in the Pacific. Our analysis indicates the ancestors of Polynesians moved through Melanesia relatively rapidly and only intermixed to a very modest degree with the indigenous populations there. The origins and current genetic relationships of Pacific Islanders have been the subjects of interest and controversy for many decades. By analyzing the variation of a large number (687) of genetic markers in almost 1,000 individuals from 41 Pacific populations, and comparing these with East Asians and others, we contribute to the clarification and resolution of many of these issues. To judge by the populations in our survey, we find that Polynesians and Micronesians have almost no genetic relation to Melanesians, but instead are strongly related to East Asians, and particularly Taiwan Aborigines. A minority of Island Melanesian populations have indications of a small shared genetic ancestry with Polynesians and Micronesians (the ones that have this tie all speak related Austronesian languages). Inland groups who speak Papuan languages are particularly divergent and internally homogeneous. The genetic divergence among Island Melanesian populations, which is neatly organized by island, island size/topography, as well as their coastal or inland locations, is remarkable for such a small region, and enlarges our understanding of the texture of contemporary human variation.

The aetiology and pathophysiology of complex diseases are driven by the interaction between genetic and environmental factors. The variability in risk and outcomes in these diseases are incompletely explained by genetics or environmental risk factors individually. Therefore, researchers are now exploring the epigenome, a biological interface at which genetics and the environment can interact. There is a growing body of evidence supporting the role of epigenetic mechanisms in complex disease pathophysiology. Epigenome-wide association studies (EWASes) investigate the association between a phenotype and epigenetic variants, most commonly DNA methylation. The decreasing cost of measuring epigenome-wide methylation and the increasing accessibility of bioinformatic pipelines have contributed to the rise in EWASes published in recent years. Here, we review the current literature on these EWASes and provide further recommendations and strategies for successfully conducting them. We have constrained our review to studies using methylation data as this is the most studied epigenetic mechanism; microarray-based data as whole-genome bisulphite sequencing remains prohibitively expensive for most laboratories; and blood-based studies due to the non-invasiveness of peripheral blood collection and availability of archived DNA, as well as the accessibility of publicly available blood-cell-based methylation data. Further, we address multiple novel areas of EWAS analysis that have not been covered in previous reviews: (1) longitudinal study designs, (2) the chip analysis methylation pipeline (ChAMP), (3) differentially methylated region (DMR) identification paradigms, (4) methylation quantitative trait loci (methQTL) analysis, (5) methylation age analysis and (6) identifying cell-specific differential methylation from mixed cell data using statistical deconvolution.

An analysis of 16 health-related quantitative traits in approximately 350,000 individuals reveals statistically significant associations between genome-wide homozygosity and four complex traits (height, lung function, cognitive ability and educational attainment); in each case increased homozygosity associates with a decreased trait value, but no evidence was seen of an influence on blood pressure, cholesterol, or ten other cardio-metabolic traits. This consortium meta-analysis of 102 cohorts and more than 350,000 individuals investigates the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity, ROH), which are inferred to be homozygous along their complete length. Focusing on 16 health-related quantitative traits, the authors find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in a second, general cognitive ability and educational attainment. In each case increased homozygosity associates with decreased trait value. No evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Homozygosity has long been associated with rare, often devastating, Mendelian disorders1, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3,4. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10−300, 2.1 × 10−6, 2.5 × 10−10 and 1.8 × 10−10, respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months’ less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5,6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

Migraine is a prevalent and debilitating disease that may, in part, arise because of disruption in neurovascular endothelia caused by elevated homocysteine. This study examined the homocysteine-lowering effects of vitamin supplementation on migraine disability, frequency and severity and whether MTHFRC677T genotype influenced treatment response. This was a randomized, double-blind placebo, controlled trial of 6 months of daily vitamin supplementation (i.e. 2 mg of folic acid, 25 mg vitamin B6, and 400 microg of vitamin B12) in 52 patients diagnosed with migraine with aura. Vitamin supplementation reduced homocysteine by 39% (approximately 4 mumol/l) compared with baseline, a reduction that was greater then placebo (P=0.001). Vitamin supplementation also reduced the prevalence of migraine disability from 60% at baseline to 30% after 6 months (P=0.01), whereas no reduction was observed for the placebo group (P>0.1). Headache frequency and pain severity were also reduced (P0.1). In this patient group the treatment effect on both homocysteine levels and migraine disability was associated with MTHFRC677T genotype whereby carriers of the C allele experienced a greater response compared with TT genotypes (P<0.05). This study provides some early evidence that lowering homocysteine through vitamin supplementation reduces migraine disability in a subgroup of patients. Larger trials are now warranted to establish whether vitamin therapy is a safe, inexpensive and effective prophylactic option for treatment of migraine and whether efficacy is dependant on MTHFRC677T genotype.