Common variants explain little of the variance of most common disease, prompting large-scale sequencing studies to understand the contribution of rare variants to these diseases. Imputation of rare variants from genom...Common variants explain little of the variance of most common disease, prompting large-scale sequencing studies to understand the contribution of rare variants to these diseases. Imputation of rare variants from genome-wide genotypic arrays offers a cost-efficient strategy to achieve necessary sample sizes required for adequate statistical power. To estimate the performance of imputation of rare variants, we imputed 153 individuals, each of whom was genotyped on 3 different genotype arrays including 317k, 610k and 1 million single nucleotide polymorphisms （SNPs）, to two different reference panels： HapMap2 and 1000 Genomes pilot March 2010 release （1KGpilot） by using IMPUTE version 2. We found that more than 94% and 84% of all SNPs yield acceptable accuracy （info 〉 0.4） in HapMap2 and 1KGpilot-based imputation, respectively. For rare variants （minor allele frequency （MAF） 〈5%）, the proportion of well- imputed SNPs increased as the MAF increased from 0.3% to 5% across all 3 genome-wide association study （GWAS） datasets. The proportion of well-imputed SNPs was 69%, 60% and 49% for SNPs with a MAF from 0.3% to 5% for 1M, 610k and 317k, respectively. None of the very rare variants （MAF 〈 0.3%） were well imputed. We conclude that the imputation accuracy of rare variants increases with higher density of genome-wide genotyping arrays when the size of the reference panel is small. Variants with lower MAF are more difficult to impute. These findings have important implications in the design and replication of large-scale sequencing studies.展开更多
Human height is a highly heritable trait in which multiple genes are involved. Recent genome-wide association studies （GWASs） have identified that COL11A1 is an important susceptibility gene for hu- man height. To d...Human height is a highly heritable trait in which multiple genes are involved. Recent genome-wide association studies （GWASs） have identified that COL11A1 is an important susceptibility gene for hu- man height. To determine whether the variants of COL11A 1 are associated with adult and children height, we analyzed splicing and coding single-nucleotide variants across COL11A1 through exome-targeted sequencing and two validation stages with a total 20,426 Chinese Han samples. A total of 105 variants were identified by exome-targeted sequencing, of which 30 SNPs were located in coding region. The strongest association signal was chrl 103380393 with P value of 4.8 × 10-7. Chrl_103380393 also showed nominal significance in the validation stage （P = 1.21×10 6）. Combined analysis of 16,738 samples strengthened the original association of chrl 103380393 with adult height （Pcombinea - 3.1×10 8）, with an increased height of 0.292sd （standard deviation） per G allele （95% CI： 0.19-0.40）. There was no evidence （P = 0.843） showing that chrl 103380393 altered child height in 3688 child samples. Only the group of 12-15 years showed slight significance with P value of 0.0258. This study firstly shows that genetic variants of COL11A1 contribute to adult height in Chinese Han population but not to children height, which expand our knowledge of the genetic factors underlying height variation and the biological regulation of human height.展开更多
Alpha1-antitrypsin deficiency is an autosomal recessive disease characterized by reduced serum levels of alpha1-antitrypsin(AAT)due to mutations in the SERPINA1 gene causing early onset pulmonary emphysema and,occasio...Alpha1-antitrypsin deficiency is an autosomal recessive disease characterized by reduced serum levels of alpha1-antitrypsin(AAT)due to mutations in the SERPINA1 gene causing early onset pulmonary emphysema and,occasionally,chronic liver disease.We report an incidental finding of a novel null AAT allele,Q0Milano,consisting of a 17 nucleotides deletion in exon 3 of SERPINA1 gene,in an Italian child with persistently increased liver enzymes,a mild decrease in circulating AAT levels and without any pulmonary disease.Q0Milano variant results in an unfunctional protein lacking of AAT active site,as the resultant protein is truncated near PiS locus involved in AAT protein stability.展开更多
Diabetes mellitus is a complicated disease characterized by a complex interplay of genetic,epigenetic,and environmental variables.It is one of the world's fastestgrowing diseases,with 783 million adults expected t...Diabetes mellitus is a complicated disease characterized by a complex interplay of genetic,epigenetic,and environmental variables.It is one of the world's fastestgrowing diseases,with 783 million adults expected to be affected by 2045.Devastating macrovascular consequences(cerebrovascular disease,cardiovascular disease,and peripheral vascular disease)and microvascular complications(like retinopathy,nephropathy,and neuropathy)increase mortality,blindness,kidney failure,and overall quality of life in individuals with diabetes.Clinical risk factors and glycemic management alone cannot predict the development of vascular problems;multiple genetic investigations have revealed a clear hereditary component to both diabetes and its related complications.In the twenty-first century,technological advancements(genome-wide association studies,nextgeneration sequencing,and exome-sequencing)have led to the identification of genetic variants associated with diabetes,however,these variants can only explain a small proportion of the total heritability of the condition.In this review,we address some of the likely explanations for this"missing heritability",for diabetes such as the significance of uncommon variants,gene-environment interactions,and epigenetics.Current discoveries clinical value,management of diabetes,and future research directions are also discussed.展开更多
SNCA,GBA,and VPS35 are three common genes associated with Parkinson's disease.Previous studies have shown that these three genes may be associated with Alzheimer's disease(AD).However,it is unclear whether the...SNCA,GBA,and VPS35 are three common genes associated with Parkinson's disease.Previous studies have shown that these three genes may be associated with Alzheimer's disease(AD).However,it is unclear whether these genes increase the risk of AD in Chinese populations.In this study,we used a targeted gene sequencing panel to screen all the exon regions and the nearby sequences of GBA,SNCA,and VPS35 in a cohort including 721 AD patients and 365 healthy controls from China.The results revealed that neither common variants nor rare variants of these three genes were associated with AD in a Chinese population.These findings suggest that the mutations in GBA,SNCA,and VPS35 are not likely to play an important role in the genetic susceptibility to AD in Chinese populations.The study was approved by the Ethics Committee of Xiangya Hospital,Central South University,China on March 9,2016(approval No.201603198).展开更多
目的评价常见罕见变异统计分析方法的统计学性质,包括一类错误和检验效能,从而为分析罕见遗传变异资料的统计方法选择提供理论依据。方法通过计算机模拟试验的方法,对SKAT(sequence kernel association test)和FPCA(functional principa...目的评价常见罕见变异统计分析方法的统计学性质,包括一类错误和检验效能,从而为分析罕见遗传变异资料的统计方法选择提供理论依据。方法通过计算机模拟试验的方法,对SKAT(sequence kernel association test)和FPCA(functional principal component analysis)等方法从一类错误和检验效能等方面进行统计学性质评价。结果SKAT方法在各种检验水准下,第一类错误率均控制在检验水准附近,且其检验效能均高于其它方法,其中SKATO(optimal unified association test)的检验效能最高。结论在罕见遗传变异统计方法中,SKATO是一种效能较高的罕见变异资料的关联分析方法。展开更多
文摘Common variants explain little of the variance of most common disease, prompting large-scale sequencing studies to understand the contribution of rare variants to these diseases. Imputation of rare variants from genome-wide genotypic arrays offers a cost-efficient strategy to achieve necessary sample sizes required for adequate statistical power. To estimate the performance of imputation of rare variants, we imputed 153 individuals, each of whom was genotyped on 3 different genotype arrays including 317k, 610k and 1 million single nucleotide polymorphisms （SNPs）, to two different reference panels： HapMap2 and 1000 Genomes pilot March 2010 release （1KGpilot） by using IMPUTE version 2. We found that more than 94% and 84% of all SNPs yield acceptable accuracy （info 〉 0.4） in HapMap2 and 1KGpilot-based imputation, respectively. For rare variants （minor allele frequency （MAF） 〈5%）, the proportion of well- imputed SNPs increased as the MAF increased from 0.3% to 5% across all 3 genome-wide association study （GWAS） datasets. The proportion of well-imputed SNPs was 69%, 60% and 49% for SNPs with a MAF from 0.3% to 5% for 1M, 610k and 317k, respectively. None of the very rare variants （MAF 〈 0.3%） were well imputed. We conclude that the imputation accuracy of rare variants increases with higher density of genome-wide genotyping arrays when the size of the reference panel is small. Variants with lower MAF are more difficult to impute. These findings have important implications in the design and replication of large-scale sequencing studies.
基金supported by the grant from the Youth National Science Foundation of China (No.31100908)
文摘Human height is a highly heritable trait in which multiple genes are involved. Recent genome-wide association studies （GWASs） have identified that COL11A1 is an important susceptibility gene for hu- man height. To determine whether the variants of COL11A 1 are associated with adult and children height, we analyzed splicing and coding single-nucleotide variants across COL11A1 through exome-targeted sequencing and two validation stages with a total 20,426 Chinese Han samples. A total of 105 variants were identified by exome-targeted sequencing, of which 30 SNPs were located in coding region. The strongest association signal was chrl 103380393 with P value of 4.8 × 10-7. Chrl_103380393 also showed nominal significance in the validation stage （P = 1.21×10 6）. Combined analysis of 16,738 samples strengthened the original association of chrl 103380393 with adult height （Pcombinea - 3.1×10 8）, with an increased height of 0.292sd （standard deviation） per G allele （95% CI： 0.19-0.40）. There was no evidence （P = 0.843） showing that chrl 103380393 altered child height in 3688 child samples. Only the group of 12-15 years showed slight significance with P value of 0.0258. This study firstly shows that genetic variants of COL11A1 contribute to adult height in Chinese Han population but not to children height, which expand our knowledge of the genetic factors underlying height variation and the biological regulation of human height.
基金Supported by The Borsa M.Coppo AISF,Italian Association for the Study of the Liver to Rametta R
文摘Alpha1-antitrypsin deficiency is an autosomal recessive disease characterized by reduced serum levels of alpha1-antitrypsin(AAT)due to mutations in the SERPINA1 gene causing early onset pulmonary emphysema and,occasionally,chronic liver disease.We report an incidental finding of a novel null AAT allele,Q0Milano,consisting of a 17 nucleotides deletion in exon 3 of SERPINA1 gene,in an Italian child with persistently increased liver enzymes,a mild decrease in circulating AAT levels and without any pulmonary disease.Q0Milano variant results in an unfunctional protein lacking of AAT active site,as the resultant protein is truncated near PiS locus involved in AAT protein stability.
文摘Diabetes mellitus is a complicated disease characterized by a complex interplay of genetic,epigenetic,and environmental variables.It is one of the world's fastestgrowing diseases,with 783 million adults expected to be affected by 2045.Devastating macrovascular consequences(cerebrovascular disease,cardiovascular disease,and peripheral vascular disease)and microvascular complications(like retinopathy,nephropathy,and neuropathy)increase mortality,blindness,kidney failure,and overall quality of life in individuals with diabetes.Clinical risk factors and glycemic management alone cannot predict the development of vascular problems;multiple genetic investigations have revealed a clear hereditary component to both diabetes and its related complications.In the twenty-first century,technological advancements(genome-wide association studies,nextgeneration sequencing,and exome-sequencing)have led to the identification of genetic variants associated with diabetes,however,these variants can only explain a small proportion of the total heritability of the condition.In this review,we address some of the likely explanations for this"missing heritability",for diabetes such as the significance of uncommon variants,gene-environment interactions,and epigenetics.Current discoveries clinical value,management of diabetes,and future research directions are also discussed.
基金supported by the National Natural Science Foundation of China,Nos.81971029 (to LS) and 82071216 (to BJ)。
文摘SNCA,GBA,and VPS35 are three common genes associated with Parkinson's disease.Previous studies have shown that these three genes may be associated with Alzheimer's disease(AD).However,it is unclear whether these genes increase the risk of AD in Chinese populations.In this study,we used a targeted gene sequencing panel to screen all the exon regions and the nearby sequences of GBA,SNCA,and VPS35 in a cohort including 721 AD patients and 365 healthy controls from China.The results revealed that neither common variants nor rare variants of these three genes were associated with AD in a Chinese population.These findings suggest that the mutations in GBA,SNCA,and VPS35 are not likely to play an important role in the genetic susceptibility to AD in Chinese populations.The study was approved by the Ethics Committee of Xiangya Hospital,Central South University,China on March 9,2016(approval No.201603198).
文摘目的评价常见罕见变异统计分析方法的统计学性质,包括一类错误和检验效能,从而为分析罕见遗传变异资料的统计方法选择提供理论依据。方法通过计算机模拟试验的方法,对SKAT(sequence kernel association test)和FPCA(functional principal component analysis)等方法从一类错误和检验效能等方面进行统计学性质评价。结果SKAT方法在各种检验水准下,第一类错误率均控制在检验水准附近,且其检验效能均高于其它方法,其中SKATO(optimal unified association test)的检验效能最高。结论在罕见遗传变异统计方法中,SKATO是一种效能较高的罕见变异资料的关联分析方法。
基金Supported by the Basic Research Expenditure of Universities in Heilongjiang Province, Speciel Fund of Heilongjiang University(KJCX201803 , KJCX201804)。
基金the National Natural Science Foundation of China(11801540)the Natural Science Foundation of Anhui(BJ2040170017)+4 种基金the Fundamental Research Funds for the Central Universities(WK2040000016)the Science and Technology Program of Guangzhou(202002030129)the Science and Technology Planning Project of Guangdong Province(2017A010101030)the National Key Research and Development Program of China(2018YFC1315400)the Third Medical Technology Projects of Shantou City in 2018(ShanFuKe【2018】128-08).
