Inference of population structure and individual ancestry is important both for population genetics and for association studies. With next generation sequencing technologies it is possible to obtain ...genetic data for all accessible genetic variations in the genome. Existing methods for admixture analysis rely on known genotypes. However, individual genotypes cannot be inferred from low-depth sequencing data without introducing errors. This article presents a new method for inferring an individual's ancestry that takes the uncertainty introduced in next generation sequencing data into account. This is achieved by working directly with genotype likelihoods that contain all relevant information of the unobserved genotypes. Using simulations as well as publicly available sequencing data, we demonstrate that the presented method has great accuracy even for very low-depth data. At the same time, we demonstrate that applying existing methods to genotypes called from the same data can introduce severe biases. The presented method is implemented in the NGSadmix software available at http://www.popgen.dk/software.
Metabolism during pregnancy is a dynamic and precisely programmed process, the failure of which can bring devastating consequences to the mother and fetus. To define a high-resolution temporal ...profile of metabolites during healthy pregnancy, we analyzed the untargeted metabolome of 784 weekly blood samples from 30 pregnant women. Broad changes and a highly choreographed profile were revealed: 4,995 metabolic features (of 9,651 total), 460 annotated compounds (of 687 total), and 34 human metabolic pathways (of 48 total) were significantly changed during pregnancy. Using linear models, we built a metabolic clock with five metabolites that time gestational age in high accordance with ultrasound (R = 0.92). Furthermore, two to three metabolites can identify when labor occurs (time to delivery within two, four, and eight weeks, AUROC ≥ 0.85). Our study represents a weekly characterization of the human pregnancy metabolome, providing a high-resolution landscape for understanding pregnancy with potential clinical utilities.
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•Weekly metabolome of maternal blood changes dynamically through healthy pregnancy•A metabolic clock of five blood metabolites accurately predicts gestational age•Two to three metabolites identify labor onset within two, four, and eight weeks•Women with metabolic clocks that outpaced ultrasound evaluation tend to deliver earlier
Identification of blood metabolites in pregnant women that can accurately predict gestational age and provide insights into pregnancy variations undetected by ultrasound.
The indigenous people of Greenland, the Inuit, have lived for a long time in the extreme conditions of the Arctic, including low annual temperatures, and with a specialized diet rich in protein and ...fatty acids, particularly omega-3 polyunsaturated fatty acids (PUFAs). A scan of Inuit genomes for signatures of adaptation revealed signals at several loci, with the strongest signal located in a cluster of fatty acid desaturases that determine PUFA levels. The selected alleles are associated with multiple metabolic and anthropometric phenotypes and have large effect sizes for weight and height, with the effect on height replicated in Europeans. By analyzing membrane lipids, we found that the selected alleles modulate fatty acid composition, which may affect the regulation of growth hormones. Thus, the Inuit have genetic and physiological adaptations to a diet rich in PUFAs.
Noninvasive blood tests that provide information about fetal development and gestational age could potentially improve prenatal care. Ultrasound, the current gold standard, is not always affordable ...in low-resource settings and does not predict spontaneous preterm birth, a leading cause of infant death. In a pilot study of 31 healthy pregnant women, we found that measurement of nine cell-free RNA (cfRNA) transcripts in maternal blood predicted gestational age with comparable accuracy to ultrasound but at substantially lower cost. In a related study of 38 women (23 full-term and 15 preterm deliveries), all at elevated risk of delivering preterm, we identified seven cfRNA transcripts that accurately classified women who delivered preterm up to 2 months in advance of labor. These tests hold promise for prenatal care in both the developed and developing worlds, although they require validation in larger, blinded clinical trials.
During the last decade genome‐wide association studies have proven to be a powerful approach to identifying disease‐causing variants. However, for admixed populations, most current methods for ...association testing are based on the assumption that the effect of a genetic variant is the same regardless of its ancestry. This is a reasonable assumption for a causal variant but may not hold for the genetic variants that are tested in genome‐wide association studies, which are usually not causal. The effects of noncausal genetic variants depend on how strongly their presence correlate with the presence of the causal variant, which may vary between ancestral populations because of different linkage disequilibrium patterns and allele frequencies. Motivated by this, we here introduce a new statistical method for association testing in recently admixed populations, where the effect size is allowed to depend on the ancestry of a given allele. Our method does not rely on accurate inference of local ancestry, yet using simulations we show that in some scenarios it gives a substantial increase in statistical power to detect associations. In addition, the method allows for testing for difference in effect size between ancestral populations, which can be used to help determine if a given genetic variant is causal. We demonstrate the usefulness of the method on data from the Greenlandic population.
Spermine oxidase (SMOX) catalyzes the oxidation of spermine to spermidine. Observational studies have reported SMOX as a source of reactive oxygen species associated with cancer, implying that ...inhibition of SMOX could be a target for chemoprevention. Here we test causality of SMOX levels with cancer risk using a Mendelian randomization analysis. We performed a GWAS of spermidine/spermine ratio to identify genetic variants associated with regulation of SMOX activity. Replication analysis was performed in two datasets of SMOX gene expression. We then did a Mendelian randomization analysis by testing the association between the SMOX genetic instrument and neuroblastoma, gastric, lung, breast, prostate, and colorectal cancers using GWAS summary statistics. GWAS of spermidine/spermine ratio identified SMOX locus (P = 1.34 × 10
) explaining 32% of the variance. The lead SNP rs1741315 was also associated with SMOX gene expression in newborns (P = 8.48 × 10
) and adults (P = 2.748 × 10
) explaining 37% and 6% of the variance, respectively. Genetically determined SMOX activity was not associated with neuroblastoma, gastric, lung, breast, prostate nor colorectal cancer (P > 0.05). A PheWAS of rs1741315 did not reveal any relevant associations. Common genetic variation in the SMOX gene was strongly associated with SMOX activity in newborns, and less strongly in adults. Genetic down-regulation of SMOX was not significantly associated with lower odds of neuroblastoma, gastric, lung, breast, prostate and colorectal cancer. These results may inform studies of SMOX inhibition as a target for chemoprevention.
Hernias are characterized by protrusion of an organ or tissue through its surrounding cavity and often require surgical repair. In this study we identify 65,492 cases for five hernia types in the UK ...Biobank and perform genome-wide association study scans for these five types and two combined groups. Our results show associated variants in all scans. Inguinal hernia has the most associations and we conduct a follow-up study with 23,803 additional cases from four study groups giving 84 independently associated variants. Identified variants from all scans are collapsed into 81 independent loci. Further testing shows that 26 loci are associated with more than one hernia type, suggesting substantial overlap between the underlying genetic mechanisms. Pathway analyses identify several genes with a strong link to collagen and/or elastin (ADAMTS6, ADAMTS16, ADAMTSL3, LOX, ELN) in the vicinity of associated loci for inguinal hernia, which substantiates an essential role of connective tissue morphology.
Introduction
Infantile hypertrophic pyloric stenosis (IHPS) is caused by hypertrophy of the pyloric sphincter muscle.
Objectives
Since previous reports have implicated lipid metabolism, we aimed to ...(1) investigate associations between IHPS and a wide array of lipid-related metabolites in newborns, and (2) address whether detected differences in metabolite levels were likely to be driven by genetic differences between IHPS cases and controls or by differences in early life feeding patterns.
Methods
We used population-based random selection of IHPS cases and controls born in Denmark between 1997 and 2014. We randomly took dried blood spots of newborns from 267 pairs of IHPS cases and controls matched by sex and day of birth. We used a mixed-effects linear regression model to evaluate associations between 148 metabolites and IHPS in a matched case–control design.
Results
The phosphatidylcholine PC(38:4) showed significantly lower levels in IHPS cases (
P
= 4.68 × 10
−8
) as did six other correlated metabolites (four phosphatidylcholines, acylcarnitine AC(2:0), and histidine). Associations were driven by 98 case–control pairs born before 2009, when median age at sampling was 6 days. No association was seen in 169 pairs born in 2009 or later, when median age at sampling was 2 days. More IHPS cases than controls had a diagnosis for neonatal difficulty in feeding at breast (
P
= 6.15 × 10
−3
). Genetic variants known to be associated with PC(38:4) levels did not associate with IHPS.
Conclusions
We detected lower levels of certain metabolites in IHPS, possibly reflecting different feeding patterns in the first days of life.
Inuit have lived for thousands of years in an extremely cold environment on a diet dominated by marine-derived fat. To investigate how this selective pressure has affected the genetic regulation of ...fatty acid metabolism, we assessed 233 serum metabolic phenotypes in a population-based sample of 1570 Greenlanders.
Using array-based and targeted genotyping, we found that rs80356779, a p.Pro479Leu variant in
, was strongly associated with markers of
-3 fatty acid metabolism, including degree of unsaturation (
=1.16×10
), levels of polyunsaturated fatty acids,
-3 fatty acids, and docosahexaoenic acid relative to total fatty acid levels (
=2.35×10
,
=4.02×10
, and
=7.92×10
). The derived allele (L479) occurred at a frequency of 76.2% in our sample while being absent in most other populations, and we found strong signatures of positive selection at the locus. Furthermore, we found that each copy of L479 reduced height by an average of 2.1 cm (
=1.04×10
). In exome sequencing data from a sister population, the Nunavik Inuit, we found no other likely causal candidate variant than rs80356779.
Our study shows that a common
missense mutation is strongly associated with a range of metabolic phenotypes and reduced height in Greenlanders. These findings are important from a public health perspective and highlight the usefulness of complex trait genetic studies in isolated populations.
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