Heritability, the proportion of phenotypic variance explained by genetic factors, can be estimated from pedigree data 1 , but such estimates are uninformative with respect to the underlying genetic architecture. Analyses of data from genome-wide association studies (GWAS) on unrelated individuals have shown that for human traits and disease, approximately one-third to two-thirds of heritability is captured by common SNPs 2-5 . It is not known whether the remaining heritability is due to the imperfect tagging of causal variants by common SNPs, in particular if the causal variants are rare, or other reasons such as overestimation of heritability from pedigree data. Here we show that pedigree heritability for height and body mass index (BMI) appears to be fully recovered from whole-genome sequence (WGS) data on 21,620 unrelated individuals of European ancestry. We assigned 47.1 million genetic variants to groups based upon their minor allele frequencies (MAF) and linkage disequilibrium (LD) with variants nearby, and estimated and partitioned variation accordingly. The estimated heritability was 0.79 (SE 0.09) for height and 0.40 (SE 0.09) for BMI, consistent with pedigree estimates. Low-MAF variants in low LD with neighbouring variants were enriched for heritability, to a greater extent for protein altering variants, consistent with negative selection thereon. Cumulatively variants in the MAF range of 0.0001 to 0.1 explained 0.54 (SE 0.05) and 0.51 (SE 0.11) of heritability for height and BMI, respectively. Our results imply that the still missing heritability of complex traits and disease is accounted for by rare variants, in particular those in regions of low LD.

Epidemiological studies of obesity, Type-2 diabetes (T2D), cardiovascular diseases and several common cancers have revealed an increased risk in Native Hawaiians compared to European- or Asian-Americans living in the Hawaiian islands. However, there remains a gap in our understanding of the genetic factors that affect the health of Native Hawaiians. To fill this gap, we studied the genetic risk factors at both the chromosomal and sub-chromosomal scales using genome-wide SNP array data on ~4,000 Native Hawaiians from the Multiethnic Cohort. We estimated the genomic proportion of Native Hawaiian ancestry (“global ancestry,” which we presumed to be Polynesian in origin), as well as this ancestral component along each chromosome (“local ancestry”) and tested their respective association with binary and quantitative cardiometabolic traits. After attempting to adjust for non-genetic covariates evaluated through questionnaires, we found that per 10% increase in global Polynesian genetic ancestry, there is a respective 8.6%, and 11.0% increase in the odds of being diabetic (P = 1.65×10−4) and having heart failure (P = 2.18×10−4), as well as a 0.059 s.d. increase in BMI (P = 1.04×10−10). When testing the association of local Polynesian ancestry with risk of disease or biomarkers, we identified a chr6 region associated with T2D. This association was driven by an uniquely prevalent variant in Polynesian ancestry individuals. However, we could not replicate this finding in an independent Polynesian cohort from Samoa due to the small sample size of the replication cohort. In conclusion, we showed that Polynesian ancestry, which likely capture both genetic and lifestyle risk factors, is associated with an increased risk of obesity, Type-2 diabetes, and heart failure, and that larger cohorts of Polynesian ancestry individuals will be needed to replicate the putative association on chr6 with T2D.

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Objectives: Studies have demonstrated that rs373863828, a missense variant in CREBRF, is associated with a number of anthropometric traits including body mass index (BMI), obesity, percent body fat, hip circumference, and abdominal circumference. Given the biological relationship between height and adiposity, we hypothesized that the effect of this variant on BMI might be due in part to an association of this variant with height. Methods: We tested the hypothesis that minor allele of rs373863828 is associated with height in a Samoan population in two adult cohorts and in a separate cohort of children (age 5-18 years old) using linear mixed modeling. Results: We found evidence of a strong relationship between rs373863828 and greater mean height in Samoan adults (0.77 cm greater average height for each copy of the minor allele) with the same direction of effect in Samoan children. Conclusions: These results suggest that the missense variant rs373863828 in CREBRF, first identified through an association with larger BMI, may be related to an underlying biological mechanism affecting overall body size including stature.

Colloidal particles interacting via a long-range repulsion can, in contrast to hard-sphere systems, exhibit crystalline ordering at low volume fraction. Here we experimentally investigate the structure and properties of such 'colloidal Wigner crystals'. We find a body-centered-cubic crystalline phase at volume fractions of φ 15%, which exhibits large fluctuations of individual particles from their average positions. We determine the three independent crystalline elastic constants, and find that these crystals are very compliant and highly anisotropic.

ObjectivesStudies have demonstrated that rs373863828, a missense mutation in CREBRF, is associated with a number of anthropometric traits including body mass index (BMI), obesity, percent body fat, hip circumference, and abdominal circumference. Given the biological relationship between height and adiposity, we hypothesized that the effect of this variant on BMI might be due in part to a previously untested association of this variant with height.MethodsWe tested the hypothesis that minor allele of rs373863828 is associated with height in a Samoan population in two adult cohorts and in a separate cohort of children (age 5 - 18 years old) using linear mixed modeling.ResultsWe found evidence of a strong relationship between rs373863828 and greater mean height in Samoan adults (0.77 cm greater average height for each copy of the minor allele) with the same direction of effect in Samoan children.ConclusionsThese results suggest that the missense variant rs373863828 in CREBRF, first identified through an association with larger BMI, may be related to an underlying biological mechanism affecting overall body size including stature.

IntroductionThe minor allele of a missense variant, rs373863828, in CREBRF is associated with higher body mass index (BMI), lower fasting glucose, and lower odds of type 2 diabetes. rs373863828 is common in Pacific Island populations (minor allele frequency (MAF) 0.096–0.259) but rare in non-Pacific Island populations (MAF <0.001). We examined the cross-sectional associations between BMI and rs373863828 in type 2 diabetes and fasting glucose with a large sample of adults of Polynesian ancestries from Samoa, American Samoa, and Aotearoa New Zealand, and estimated the direct and indirect (via BMI) effects of rs373863828 on type 2 diabetes and fasting glucose.Research design and methodsWe regressed type 2 diabetes and fasting glucose on BMI and rs373863828 stratified by obesity, regressed type 2 diabetes and fasting glucose on BMI stratified by rs373863828 genotype, and assessed the effects of rs373863828 on type 2 diabetes and fasting glucose with path analysis. The regression analyses were completed separately in four samples that were recruited during different time periods between 1990 and 2010 and then the results were meta-analyzed. All samples were pooled for the path analysis.ResultsAssociation of BMI with type 2 diabetes and fasting glucose may be greater in those without obesity (OR=7.77, p=0.015 and β=0.213, p=9.53×10−5, respectively) than in those with obesity (OR=5.01, p=1.12×10−9 and β=0.162, p=5.63×10−6, respectively). We did not observe evidence of differences in the association of BMI with type 2 diabetes or fasting glucose by genotype. In the path analysis, the minor allele has direct negative (lower odds of type 2 diabetes and fasting glucose) and indirect positive (higher odds of type 2 diabetes and fasting glucose) effects on type 2 diabetes risk and fasting glucose, with the indirect effects mediated through a direct positive effect of rs373863828 on BMI.ConclusionsThere may be a stronger effect of BMI on fasting glucose in Polynesian individuals without obesity than in those with obesity. Carrying the rs373863828 minor allele does not decouple higher BMI from higher odds of type 2 diabetes.

24Epidemiological studies of obesity, Type-2 diabetes (T2D), cardiovascular 25 diseases and several common cancers have revealed an increased risk in Native 26Hawaiians compared to European-or Asian-Americans living in the Hawaiian islands. 27However, there remains a gap in our understanding of the genetic factors that affect the 28 health of Native Hawaiians. To fill this gap, we studied the genetic risk factors at both the 29 chromosomal and sub-chromosomal scales using genome-wide SNP array data on 30 ~4,000 Native Hawaiians from the Multiethnic Cohort. We estimated the genomic 31 proportion of Native Hawaiian ancestry ("global ancestry," which we presumed to be 32Polynesian in origin), as well as this ancestral component along each chromosome ("local 33 ancestry") and tested their respective association with binary and quantitative 34 cardiometabolic traits. After attempting to adjust for non-genetic covariates evaluated 35 through questionnaires, we found that per 10% increase in global Polynesian genetic 36 ancestry, there is a respective 8.6%, and 11.0% increase in the odds of being diabetic (P 37 = 1.65 10 -4 ) and having heart failure (P = 2.18 10 -4 ), as well as a 0.059 s.d. increase in 38 BMI (P = 1.04 10 -10 ). When testing the association of local Polynesian ancestry with risk 39 of disease or biomarkers, we identified a chr6 region associated with T2D. This 40 association was driven by an uniquely prevalent variant in Polynesian ancestry individuals. 41However, we could not replicate this finding in an independent Polynesian cohort from 42 Samoa due to the small sample size of the replication cohort. In conclusion, we showed 43 that Polynesian ancestry, which likely capture both genetic and lifestyle risk factors, is 44 associated with an increased risk of obesity, Type-2 diabetes, and heart failure, and that 45 3 larger cohorts of Polynesian ancestry individuals will be needed to replicate the putative 46 association on chr6 with T2D. 47 48 Author Summary 49Native Hawaiians are one of the fastest growing ethnic minority in the U.S., and exhibit 50 increased risk for metabolic and cardiovascular diseases. However, they are generally 51 understudied, especially from a genetic perspective. To fill this gap, we studied the 52 association of Polynesian genetic ancestry, at genomic and subgenomic scale, with 53 quantitative and binary traits in self-identified Native Hawaiians. We showed that 54Polynesian ancestry, which likely capture both genetic and non-genetic risk factors 55 related to Native Hawaiian people and culture are associated with increased risk for 56 obesity, type-2 diabetes, and heart failure. While we do not endorse utilizing genetic 57 information to supplant current standards of defining community membership through 58 self-identity or genealogical records, our results suggest future studies could identify 59 population-specific genetic susceptibility factors that may be useful in suggesting 60 underlying biological mechanisms and reducing the disparity in disease interventions i...