不宁腿综合征的连锁和关联分析
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摘要
不宁腿综合征(Restless Legs Syndrome, RLS)是一种常见的神经性疾病,它主要的特征为有强烈运动肢体的愿望,并伴随肢体感觉异常；症状在夜间或休息时会加重；但是通过运动能暂时缓解症状。它严重危害着患者正常的休息,影响他们的健康和生活质量。流行病学研究表明不宁腿综合征在高加索人群中发病率为5%-24%,这一发病率远高于在亚洲和非洲人群中的发病率(0.1%-3.9%),这暗示种族因素可能在RLS的发生中有作用。而且不宁腿综合征在女性的发病率约为男性的2倍。45%-65%的不宁腿综合征患者都有阳性家族史,对双胞胎的研究表明同卵双胞胎具有高度的一致性。这提示遗传因素在RLS的发病机制中有重要作用。通过家系连锁分析已报道7个不宁腿综合征的遗传位点,分别是12q12-q21,14q13-21,9p24-p22,2q33,20p13,19p13和16p12.1,但是至今还没有在这些位点中发现引起疾病的突变。最近利用大量单核苷酸多态性(SNP)进行的全基因组关联分析发现了另外4个与不宁腿综合征相关的易感位点MEIS1, BTBD9, MAP2K5/SKOR1或MAP2K5/LBXCOR1, PTPRD,其中PTPRD基因位于9p24-p22区域内。而在连锁区域12q12-q21的关联分析发现了另一个RLS的易感基因nNOS。
本课题主要从连锁分析和关联分析两方面来对不宁腿综合征进行分子遗传学的研究,包括以下3个部分：
(1)对15个美国RLS家系进行连锁分析
在15个美国RLS家系中使用中密度的微卫星标记进行全基因组扫描,用genehunter plus软件对连锁进行统计分析以HLOD值表示。HLOD计算在显性和隐性两种模式下进行。根据全基因组连锁分析的结果,我们在相应的位点增加了微卫星标记进行进一步的定位。全基因组的连锁分析显示在隐性模式下4号染色体与不宁腿综合征连锁(HLOD>3)。在显性模式下3号和5号染色体与不宁腿综合征连锁(HLOD>2)。进一步的连锁分析将3个连锁位点缩小在6cM内,三个位点分别为：3q25.1,4q34.5-35.1,5p15.33。4q34.5-35.1区段最大的多点HLOD值为3.55,单点HLOD最大值为2.54位于D4S17。3q25.1区段最大的多点HLOD值为2.2,单点HLOD最大值为2.36位于D3S1299；5p15.33区段,多点HLOD值最大为2.79,单点HLOD最大值为2.54位于D5S2005。本研究首次发现3个新的不宁腿综合征连锁位点。
(2)在15个美国RLS家系和189病人/560对照中检测PTPRD与RLS的相关性
PTPRD基因编码酪氨酸磷酸酶受体D,位于9p24-p22连锁位点内,为了检测PTPRD是否与RLS相关,我使用了位于PTPRD基因非编码区的2个SNP rs1975197和rs4626664在189 RLS病人/560对照中进行群体关联分析,同时在15个RLS家系进行家系关联分析来检测美国高加索人群中PTPRD与RLS的关联性。我们还在15个家系的先症者中进行了PTPRD基因外显子和外显子内含子结合区测序。rsl975197与不宁腿综合征相关性在群体关联分析中得到了很好的重复(等位基因关联分析P=0.0004,odds ratio=1.68；基因型关联分析中累积模式下.P=0.0013,显性模式下P=0.0003),rs4626664仅在等位基因关联分析中与不宁腿综合征相关。家系关联分析表明rs1975197与不宁腿综合征相关(P=0.015),而rs4626664与不宁腿综合征无关(P=0.622)。对PTPRD基因测序在39号外显子发现了一个罕见的p.E1639D变化,但是这个变化在家系中与不宁腿综合征没有共分离,表明这一变化不是RLS的致病突变。本研究首次独立地在美国人群中重复了PTPRD基因与RLS的相关性,群体关联分析和家系关联分析都表明PTPRD基因上的SNP rs1975197赋予了RLS患病风险。
(3)在38个美国RLS家系和189病人/560对照中检测MEIS1,BTBD9, MAP2K5/SKOR1与RLS的相关性
最近的全基因组关联分析鉴定了3个RLS的易感位点,但是全基因组关联分析的结果需要在多个人群中重复才能进一步确定这些位点对RLS的作用。因此我在上述的美国群体中展开群体关联分析对MEIS1,BTBD9和MAP2K5/SKOR1与RLS的相关性进行判断,并在38个RLS家系中进行家系关联分析。rs2300478,rs9357271和rs1026732分别位于MEIS1,BTBD9,和MAP2K5/SKOR1三个位点。群体关联分析表明这三个SNP都与RLS相关(rs2300478,rs9357271和rs1026732的P值和OR值分别为P=0.0001/OR=1.65,P=0.0021/OR=1.11,P=0.0011/OR=1.14),家系关联分析显示只有rs1026732与RLS显著相关。总的来说MEIS1,BTBD9和MAP2K5/SKOR1位点上的SNP在美国人群中与RLS的发生有关。本研究为MEIS1, BTBD9和MAP2K5/SKOR1与RLS在美国人群中相关提供了证据,并且首次以家系关联分析的方法确定了MAP2K5/SKOR1与RLS的相关性。
Restless legs syndrome (RLS) is a common neurological disorder characterized by an urge to move the limbs, and is usually accompanied by uncomfortable sensations that worsen with rest, improve with movement, and are worse in the evening or night. It can impair sleep and adversely affects health and quality of life. Epidemiological studies of RLS revealed a prevalence rate of 5%-24% in Caucasian populations, which is much higher than the rate in Asian and African populations (0.1%-3.9%), suggesting a possible role for ethnic factors in the occurrence of RLS. Furthermore, RLS is twice more common in females than in males. RLS is associated with a positive family history in 45% to 65% of patients and twin studies showed a high concordant rate in monozygotic twins4. All these results suggest that genetic factors play an important role in the pathogenesis of RLS. Seven genetics loci for RLS have been reported. These loci were identified by linkage analysis in families, and include RLS1 on chromosome 12ql2-q21, RLS2 on 14q13-21, RLS3 on 9p24-p22, RLS4 on 2q33, RLS5 on 20p13, RLS6 on 19p13 and RLS7 on 16p12.1. To date, no disease-causing mutations from these loci have been reported. Recent genome-wide association studies (GWAS) using 500,000 to a million single nucleotide polymorphisms (SNPs) identified four additional genetic loci that are associated with RLS. The identified GWAS loci are represented by SNPs on chromosome 2p14 (MEIS1), 6p21.2 (BTBD9),15q23(MAP2K5/SKOR1 or MAP2K5/LBXCOR1), and 9p24.1-p23 (PTPRD) which overlaps with RLS3. And the association studies in linkage region RLS1 identified nNOS as a gene being associated with RLS.
In this project, I have carried out molecular genetics studies for RLS using linkage analysis and association studies. There are three major areas for this project.
Part 1 Linkage analysis was performed in 15 U.S. RLS families
I performed a genome-wide genetic linkage scan in 15 multiplex families using 400 marker loci with a mean spacing of 10 cM. I used Genehunter Plus to generate linkage statistics, expressed as heterogeneity (HLOD) scores, under dominant and recessive genetic models. I then used fine mapping to characterize the positive linkage regions with additional markers within these regions. Genome-wide linkage analysis showed a linkage signal on chromosome 4 with a recessive inheritance model (HLOD>3) and a suggestive linkage on chromosome 3 and 5 with a dominant inheritance model (HLOD>2). After fine mapping, the 4q34.5-35.1 keeps linkage was defined within a region from 194.3cM to 200cM (HLOD>3). The peak multipoint HLOD was 3.55 and single point HLODmax was 2.54 at D4S171; the maxima multipoint HLOD was 2.2 in the suggestive linkage region on 3q25.1(166.5-169cM) and single point HLODmax was 2.36 at D3S1299; the maxima multipoint HLOD for 5p15.33 locus(1.7-7.7cM) was 2.79 and single point HLODmax was 2.54 at D5S2005. This study identifies one novel RLS susceptibility locus on 4q34.5-35.1 and two suggestive RLS loci on 3q25.1and 5p15.33.
Part 2 Association study between PTPRD and RLS in 15 U.S. RLS families and 189cases/560controls
The PTPRD gene encoding protein tyrosine phosphatase receptor type D became a strong candidate gene for RLS at the RLS3 locus. To test whether PTPRD is associated with RLS, I performed population-based association study using two intronic SNPs rs1975197 and rs4626664 in PTPRD in a case control cohort of 189 patients and 560 controls; I also performed a family-based association study in 15 multiplex families to assess the association between PTPRD and RLS in an American Caucasian population. Moreover direct DNA sequence analysis was carried out to screen coding exons and exon-intron boundaries of PTPRD for rare mutations in 15 probands. The association between RLS and rs 1975197 was significant in the population-based case control association study (allelic P=0.0004, odds ratio=1.68; genotypic P=0.0013 and 0.0003 for an additive and dominant model, respectively). SNP rs4626664 is associated with RLS only in the allelic association study (P=0.023). A family-based sibling transmission disequilibrium test showed association of RLS with SNP rs1975197 (P=0.015), but not with rs4626664 (P=0.622). One rare p.E1639D variant was identified in exon 39 in kindred RLS40005. The rare D1639 allele did not co-segregate with RLS in the family, suggesting that p.E1639D variant is not a causative mutation. This represents the first independent study to validate the association between PTPRD variants and RLS. Both family-based and population-based association studies suggest that PTPRD variant rs1975197 confers risk of RLS.
Part 3 Association study between MEIS1, BTBD9, MAP2K5/SKOR1 and RLS in 38 U.S. RLS families and 189 cases/560 controls
Recent GWAS identified three additional loci for RLS. But, GWAS results need to be replicated in as many populations as possible. We assessed these GWAS loci using the same population as used for the PTPRD study. We investigated three variants, rs2300478 in MEIS1, rs9357271 in BTBD9, and rs1026732 in MAP2K5/SKOR1 in 38 RLS families and 189 RLS patients/560 controls from the U.S. for their association with RLS. Both family-based and population-based case-control association studies were carried out. Case-control association studies showed significant association between all three variants and RLS (P=0.0001/OR=1.65, P=0.0021/OR=1.11, P=0.0011/OR=1.14 for rs2300478, rs9357271, and rs1026732, respectively). The family-based study showed that SNP rs1026732 in MAP2K5/SKOR1 was significantly associated with RLS (P=0.01). In conclusion, variants in MEIS1, BTBD9, and MAP2K5/SKOR1 confer a significant risk of RLS in a U.S. population. The study provided evidences to support the association of MEIS1, BTBD9, and MAP2K5/SKOR1 and RLS in an American Caucasian population. This is the firstly family-based association study to identify the association between MAP2K5/SKOR1 and RLS.
本课题主要从连锁分析和关联分析两方面来对不宁腿综合征进行分子遗传学的研究,包括以下3个部分：
(1)对15个美国RLS家系进行连锁分析
在15个美国RLS家系中使用中密度的微卫星标记进行全基因组扫描,用genehunter plus软件对连锁进行统计分析以HLOD值表示。HLOD计算在显性和隐性两种模式下进行。根据全基因组连锁分析的结果,我们在相应的位点增加了微卫星标记进行进一步的定位。全基因组的连锁分析显示在隐性模式下4号染色体与不宁腿综合征连锁(HLOD>3)。在显性模式下3号和5号染色体与不宁腿综合征连锁(HLOD>2)。进一步的连锁分析将3个连锁位点缩小在6cM内,三个位点分别为：3q25.1,4q34.5-35.1,5p15.33。4q34.5-35.1区段最大的多点HLOD值为3.55,单点HLOD最大值为2.54位于D4S17。3q25.1区段最大的多点HLOD值为2.2,单点HLOD最大值为2.36位于D3S1299；5p15.33区段,多点HLOD值最大为2.79,单点HLOD最大值为2.54位于D5S2005。本研究首次发现3个新的不宁腿综合征连锁位点。
(2)在15个美国RLS家系和189病人/560对照中检测PTPRD与RLS的相关性
PTPRD基因编码酪氨酸磷酸酶受体D,位于9p24-p22连锁位点内,为了检测PTPRD是否与RLS相关,我使用了位于PTPRD基因非编码区的2个SNP rs1975197和rs4626664在189 RLS病人/560对照中进行群体关联分析,同时在15个RLS家系进行家系关联分析来检测美国高加索人群中PTPRD与RLS的关联性。我们还在15个家系的先症者中进行了PTPRD基因外显子和外显子内含子结合区测序。rsl975197与不宁腿综合征相关性在群体关联分析中得到了很好的重复(等位基因关联分析P=0.0004,odds ratio=1.68；基因型关联分析中累积模式下.P=0.0013,显性模式下P=0.0003),rs4626664仅在等位基因关联分析中与不宁腿综合征相关。家系关联分析表明rs1975197与不宁腿综合征相关(P=0.015),而rs4626664与不宁腿综合征无关(P=0.622)。对PTPRD基因测序在39号外显子发现了一个罕见的p.E1639D变化,但是这个变化在家系中与不宁腿综合征没有共分离,表明这一变化不是RLS的致病突变。本研究首次独立地在美国人群中重复了PTPRD基因与RLS的相关性,群体关联分析和家系关联分析都表明PTPRD基因上的SNP rs1975197赋予了RLS患病风险。
(3)在38个美国RLS家系和189病人/560对照中检测MEIS1,BTBD9, MAP2K5/SKOR1与RLS的相关性
最近的全基因组关联分析鉴定了3个RLS的易感位点,但是全基因组关联分析的结果需要在多个人群中重复才能进一步确定这些位点对RLS的作用。因此我在上述的美国群体中展开群体关联分析对MEIS1,BTBD9和MAP2K5/SKOR1与RLS的相关性进行判断,并在38个RLS家系中进行家系关联分析。rs2300478,rs9357271和rs1026732分别位于MEIS1,BTBD9,和MAP2K5/SKOR1三个位点。群体关联分析表明这三个SNP都与RLS相关(rs2300478,rs9357271和rs1026732的P值和OR值分别为P=0.0001/OR=1.65,P=0.0021/OR=1.11,P=0.0011/OR=1.14),家系关联分析显示只有rs1026732与RLS显著相关。总的来说MEIS1,BTBD9和MAP2K5/SKOR1位点上的SNP在美国人群中与RLS的发生有关。本研究为MEIS1, BTBD9和MAP2K5/SKOR1与RLS在美国人群中相关提供了证据,并且首次以家系关联分析的方法确定了MAP2K5/SKOR1与RLS的相关性。
Restless legs syndrome (RLS) is a common neurological disorder characterized by an urge to move the limbs, and is usually accompanied by uncomfortable sensations that worsen with rest, improve with movement, and are worse in the evening or night. It can impair sleep and adversely affects health and quality of life. Epidemiological studies of RLS revealed a prevalence rate of 5%-24% in Caucasian populations, which is much higher than the rate in Asian and African populations (0.1%-3.9%), suggesting a possible role for ethnic factors in the occurrence of RLS. Furthermore, RLS is twice more common in females than in males. RLS is associated with a positive family history in 45% to 65% of patients and twin studies showed a high concordant rate in monozygotic twins4. All these results suggest that genetic factors play an important role in the pathogenesis of RLS. Seven genetics loci for RLS have been reported. These loci were identified by linkage analysis in families, and include RLS1 on chromosome 12ql2-q21, RLS2 on 14q13-21, RLS3 on 9p24-p22, RLS4 on 2q33, RLS5 on 20p13, RLS6 on 19p13 and RLS7 on 16p12.1. To date, no disease-causing mutations from these loci have been reported. Recent genome-wide association studies (GWAS) using 500,000 to a million single nucleotide polymorphisms (SNPs) identified four additional genetic loci that are associated with RLS. The identified GWAS loci are represented by SNPs on chromosome 2p14 (MEIS1), 6p21.2 (BTBD9),15q23(MAP2K5/SKOR1 or MAP2K5/LBXCOR1), and 9p24.1-p23 (PTPRD) which overlaps with RLS3. And the association studies in linkage region RLS1 identified nNOS as a gene being associated with RLS.
In this project, I have carried out molecular genetics studies for RLS using linkage analysis and association studies. There are three major areas for this project.
Part 1 Linkage analysis was performed in 15 U.S. RLS families
I performed a genome-wide genetic linkage scan in 15 multiplex families using 400 marker loci with a mean spacing of 10 cM. I used Genehunter Plus to generate linkage statistics, expressed as heterogeneity (HLOD) scores, under dominant and recessive genetic models. I then used fine mapping to characterize the positive linkage regions with additional markers within these regions. Genome-wide linkage analysis showed a linkage signal on chromosome 4 with a recessive inheritance model (HLOD>3) and a suggestive linkage on chromosome 3 and 5 with a dominant inheritance model (HLOD>2). After fine mapping, the 4q34.5-35.1 keeps linkage was defined within a region from 194.3cM to 200cM (HLOD>3). The peak multipoint HLOD was 3.55 and single point HLODmax was 2.54 at D4S171; the maxima multipoint HLOD was 2.2 in the suggestive linkage region on 3q25.1(166.5-169cM) and single point HLODmax was 2.36 at D3S1299; the maxima multipoint HLOD for 5p15.33 locus(1.7-7.7cM) was 2.79 and single point HLODmax was 2.54 at D5S2005. This study identifies one novel RLS susceptibility locus on 4q34.5-35.1 and two suggestive RLS loci on 3q25.1and 5p15.33.
Part 2 Association study between PTPRD and RLS in 15 U.S. RLS families and 189cases/560controls
The PTPRD gene encoding protein tyrosine phosphatase receptor type D became a strong candidate gene for RLS at the RLS3 locus. To test whether PTPRD is associated with RLS, I performed population-based association study using two intronic SNPs rs1975197 and rs4626664 in PTPRD in a case control cohort of 189 patients and 560 controls; I also performed a family-based association study in 15 multiplex families to assess the association between PTPRD and RLS in an American Caucasian population. Moreover direct DNA sequence analysis was carried out to screen coding exons and exon-intron boundaries of PTPRD for rare mutations in 15 probands. The association between RLS and rs 1975197 was significant in the population-based case control association study (allelic P=0.0004, odds ratio=1.68; genotypic P=0.0013 and 0.0003 for an additive and dominant model, respectively). SNP rs4626664 is associated with RLS only in the allelic association study (P=0.023). A family-based sibling transmission disequilibrium test showed association of RLS with SNP rs1975197 (P=0.015), but not with rs4626664 (P=0.622). One rare p.E1639D variant was identified in exon 39 in kindred RLS40005. The rare D1639 allele did not co-segregate with RLS in the family, suggesting that p.E1639D variant is not a causative mutation. This represents the first independent study to validate the association between PTPRD variants and RLS. Both family-based and population-based association studies suggest that PTPRD variant rs1975197 confers risk of RLS.
Part 3 Association study between MEIS1, BTBD9, MAP2K5/SKOR1 and RLS in 38 U.S. RLS families and 189 cases/560 controls
Recent GWAS identified three additional loci for RLS. But, GWAS results need to be replicated in as many populations as possible. We assessed these GWAS loci using the same population as used for the PTPRD study. We investigated three variants, rs2300478 in MEIS1, rs9357271 in BTBD9, and rs1026732 in MAP2K5/SKOR1 in 38 RLS families and 189 RLS patients/560 controls from the U.S. for their association with RLS. Both family-based and population-based case-control association studies were carried out. Case-control association studies showed significant association between all three variants and RLS (P=0.0001/OR=1.65, P=0.0021/OR=1.11, P=0.0011/OR=1.14 for rs2300478, rs9357271, and rs1026732, respectively). The family-based study showed that SNP rs1026732 in MAP2K5/SKOR1 was significantly associated with RLS (P=0.01). In conclusion, variants in MEIS1, BTBD9, and MAP2K5/SKOR1 confer a significant risk of RLS in a U.S. population. The study provided evidences to support the association of MEIS1, BTBD9, and MAP2K5/SKOR1 and RLS in an American Caucasian population. This is the firstly family-based association study to identify the association between MAP2K5/SKOR1 and RLS.
引文
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