A major use of the 1000 Genomes Project (1000 GP) data is genotype imputation in genome-wide association studies (GWAS). Here we develop a method to estimate haplotypes from low-coverage sequencing ...data that can take advantage of single-nucleotide polymorphism (SNP) microarray genotypes on the same samples. First the SNP array data are phased to build a backbone (or 'scaffold') of haplotypes across each chromosome. We then phase the sequence data 'onto' this haplotype scaffold. This approach can take advantage of relatedness between sequenced and non-sequenced samples to improve accuracy. We use this method to create a new 1000 GP haplotype reference set for use by the human genetic community. Using a set of validation genotypes at SNP and bi-allelic indels we show that these haplotypes have lower genotype discordance and improved imputation performance into downstream GWAS samples, especially at low-frequency variants.
Kim et al. identify novel genes and disease pathways in the forebrain developmental disorder holoprosencephaly, and show that many cases involve oligogenic inheritance. The findings underline the ...roles of Sonic Hedgehog and primary cilia in forebrain development, and show that integrating clinical phenotyping into genetic studies can uncover relevant mutations.
Abstract
Holoprosencephaly is a pathology of forebrain development characterized by high phenotypic heterogeneity. The disease presents with various clinical manifestations at the cerebral or facial levels. Several genes have been implicated in holoprosencephaly but its genetic basis remains unclear: different transmission patterns have been described including autosomal dominant, recessive and digenic inheritance. Conventional molecular testing approaches result in a very low diagnostic yield and most cases remain unsolved. In our study, we address the possibility that genetically unsolved cases of holoprosencephaly present an oligogenic origin and result from combined inherited mutations in several genes. Twenty-six unrelated families, for whom no genetic cause of holoprosencephaly could be identified in clinical settings whole exome sequencing and comparative genomic hybridization (CGH)-array analyses, were reanalysed under the hypothesis of oligogenic inheritance. Standard variant analysis was improved with a gene prioritization strategy based on clinical ontologies and gene co-expression networks. Clinical phenotyping and exploration of cross-species similarities were further performed on a family-by-family basis. Statistical validation was performed on 248 ancestrally similar control trios provided by the Genome of the Netherlands project and on 574 ancestrally matched controls provided by the French Exome Project. Variants of clinical interest were identified in 180 genes significantly associated with key pathways of forebrain development including sonic hedgehog (SHH) and primary cilia. Oligogenic events were observed in 10 families and involved both known and novel holoprosencephaly genes including recurrently mutated FAT1, NDST1, COL2A1 and SCUBE2. The incidence of oligogenic combinations was significantly higher in holoprosencephaly patients compared to two control populations (P < 10−9). We also show that depending on the affected genes, patients present with particular clinical features. This study reports novel disease genes and supports oligogenicity as clinically relevant model in holoprosencephaly. It also highlights key roles of SHH signalling and primary cilia in forebrain development. We hypothesize that distinction between different clinical manifestations of holoprosencephaly lies in the degree of overall functional impact on SHH signalling. Finally, we underline that integrating clinical phenotyping in genetic studies is a powerful tool to specify the clinical relevance of certain mutations.
Many common illnesses differentially affect men and women for unknown reasons. The autoimmune diseases lupus and Sjögren’s syndrome affect nine times more women than men
1
, whereas schizophrenia ...affects men more frequently and severely
2
. All three illnesses have their strongest common genetic associations in the Major Histocompatibility Complex (MHC) locus, an association that in lupus and Sjögren’s syndrome has long been thought to arise from alleles of the human leukocyte antigen (
HLA
) genes at that locus
3
–
6
. Here we show that the complement component 4 (
C4
) genes, which are also in the MHC locus and were recently found to increase risk for schizophrenia
7
, generate 7-fold variation in risk for lupus (95% CI: 5.88–8.61;
p
< 10
−117
in total) and 16-fold variation in risk for Sjögren’s syndrome (95% CI: 8.59–30.89;
p
< 10
−23
in total) among individuals with common
C4
genotypes, with
C4A
protecting more strongly than
C4B
in both illnesses. The same alleles that increase risk for schizophrenia greatly reduced risk for lupus and Sjögren’s syndrome. In all three illnesses,
C4
alleles acted more strongly in men than in women: common combinations of
C4A
and
C4B
generated 14-fold variation in risk for lupus, 31-fold variation in risk for Sjögren’s syndrome, and 1.7-fold variation in schizophrenia risk among men (vs. 6-fold, 15-fold, and 1.26-fold among women respectively). At a protein level, both C4 and its effector C3 were present at greater levels in men than women in cerebrospinal fluid (
p
< 10
−5
for both C4 and C3) and plasma
8
,
9
among adults ages 20–50, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help explain the larger effects of
C4
alleles in men, women’s greater risk of SLE and Sjögren’s, and men’s greater vulnerability in schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.
The selective pressures that shape clonal evolution in healthy individuals are largely unknown. Here we investigate 8,342 mosaic chromosomal alterations (mCAs) of length 50kb–249Mb that we uncovered ...in blood-derived DNA from 151,202 UK Biobank participants using new phase-based computational techniques (estimated false discovery rate, 6–9%). We found six loci at which inherited variants associated strongly with the acquisition of deletions or loss of heterozygosity in
cis
. At three such loci (
MPL
,
TM2D3
/
TARSL2
, and
FRA10B
), we identified a likely causal variant that acted with high penetrance (5–50%). Inherited alleles at one locus appeared to affect the probability of somatic mutation, and at three other loci to be objects of positive or negative clonal selection. Several specific mCAs strongly associated with future hematological malignancies. Our results reveal a multitude of paths toward clonal expansions with a wide range of effects on human health.
Population differentiation has proved to be effective for identifying loci under geographically localized positive selection, and has the potential to identify loci subject to balancing selection. We ...have previously investigated the pattern of genetic differentiation among human populations at 36.8 million genomic variants to identify sites in the genome showing high frequency differences. Here, we extend this dataset to include additional variants, survey sites with low levels of differentiation, and evaluate the extent to which highly differentiated sites are likely to result from selective or other processes.
We demonstrate that while sites with low differentiation represent sampling effects rather than balancing selection, sites showing extremely high population differentiation are enriched for positive selection events and that one half may be the result of classic selective sweeps. Among these, we rediscover known examples, where we actually identify the established functional SNP, and discover novel examples including the genes ABCA12, CALD1 and ZNF804, which we speculate may be linked to adaptations in skin, calcium metabolism and defense, respectively.
We identify known and many novel candidate regions for geographically restricted positive selection, and suggest several directions for further research.
Large-scale studies spanning diverse project sites, populations, languages, and measurements are increasingly important to relate psychological to biological variables. National and international ...consortia already are collecting and executing mega-analyses on aggregated data from individuals, with different measures on each person. In this research, we show that Asparouhov and Muthén’s alignment method can be adapted to align data from disparate item sets and response formats. We argue that with these adaptations, the alignment method is well suited for combining data across multiple sites even when they use different measurement instruments. The approach is illustrated using data from the Whole Genome Sequencing in Psychiatric Disorders consortium and a real-data-based simulation is used to verify accurate parameter recovery. Factor alignment appears to increase precision of measurement and validity of scores with respect to external criteria. The resulting parameter estimates may further inform development of more effective and efficient methods to assess the same constructs in prospectively designed studies.
Thousands of genome segments appear to be present in widely varying copy number in different human genomes. We developed ways to use increasingly abundant whole genome sequence data to identify the ...copy numbers, alleles and haplotypes present at most large, multi-allelic CNVs (mCNVs). We analyzed 849 genomes sequenced by the 1000 Genomes Project to identify most large (>5 kb) mCNVs, including 3,878 duplications, of which 1,356 appear to have three or more segregating alleles. We find that mCNVs give rise to most human gene-dosage variation – exceeding sevenfold the contribution of deletions and biallelic duplications – and that this variation in gene dosage generates abundant variation in gene expression. We describe “runaway duplication haplotypes” in which genes, including
HPR
and
ORM1
, have mutated to high copy number on specific haplotypes. We describe partially successful initial strategies for analyzing mCNVs via imputation and provide an initial data resource to support such analyses.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Co-inheritance of alpha-thalassemia has a significant protective effect on the severity of complications of sickle cell disease (SCD), including stroke. However, little information exists on the ...association and interactions for the common African ancestral alpha-thalassemia mutation (-alpha3.7 deletion) and beta-globin traits (HbS trait SCT and HbC trait) on important clinical phenotypes such as red blood cell parameters, anemia, and chronic kidney disease (CKD). In a community-based cohort of 2,916 African Americans from the Jackson Heart Study, we confirmed the expected associations between SCT, HbC trait, and the -alpha3.7 deletion with lower mean corpuscular volume/mean corpuscular hemoglobin and higher red blood cell count and red cell distribution width. In addition to the recently recognized association of SCT with lower estimated glomerular filtration rate and glycated hemoglobin (HbA1c), we observed a novel association of the -alpha3.7 deletion with higher HbA1c levels. Co-inheritance of each additional copy of the -alpha3.7 deletion significantly lowered the risk of anemia and chronic kidney disease among individuals with SCT (P-interaction = 0.031 and 0.019, respectively). Furthermore, co-inheritance of a novel alpha-globin regulatory variant was associated with normalization of red cell parameters in individuals with the -alpha3.7 deletion and significantly negated the protective effect of alpha-thalassemia on stroke in 1,139 patients with sickle cell anemia from the Cooperative Study of Sickle Cell Disease (CSSCD) (P-interaction = 0.0049). Functional assays determined that rs11865131, located in the major alpha-globin enhancer MCS-R2, was the most likely causal variant. These findings suggest that common alpha- and beta-globin variants interact to influence hematologic and clinical phenotypes in African Americans, with potential implications for risk-stratification and counseling of individuals with SCD and SCT.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The original version of this article contained an error in the name of the author Ramachandran S. Vasan, which was incorrectly given as Vasan S. Ramachandran. This has now been corrected in both the ...PDF and HTML versions of the article.
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