Genome-wide association study reveals greater polygenic loading for schizophrenia in cases with a family history of illness.
Genome-wide association study reveals greater polygenic loading for schizophrenia in cases with a family history of illness.
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DOI：
10.1002/ajmg.b.32402
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发表时间：
2016-03
期刊：
影响因子：
--
通讯作者：
Schizophrenia Working Group of the Psychiatric Genomics Consortium
中科院分区：
文献类型：
--
作者：
Bigdeli TB;Ripke S;Bacanu SA;Lee SH;Wray NR;Gejman PV;Rietschel M;Cichon S;St Clair D;Corvin A;Kirov G;McQuillin A;Gurling H;Rujescu D;Andreassen OA;Werge T;Blackwood DH;Pato CN;Pato MT;Malhotra AK;O'Donovan MC;Kendler KS;Fanous AH;Schizophrenia Working Group of the Psychiatric Genomics Consortium
精神分裂症的全基因组关联研究（GWAS）已经产生了100多种常见的易感性变异，并强烈支持大量小等位基因效应的实质性多基因贡献。据推测，家族性精神分裂症在很大程度上是遗传因素的结果，而不是环境因素。我们调查了精神分裂症的家族性在多大程度上与在大型GWAS中可检测到的常见风险变异的富集相关。我们分析了精神病基因组学联盟（PGC 1）精神分裂症研究中报告有精神病家族史的病例（N = 978）、报告无此类家族史的病例（N = 4，503）和未筛选的对照（N = 8，285）的单核苷酸多态性（SNP）数据。我们使用了多项逻辑回归方法与模型拟合，以检测等位基因的影响，具体到任何一个家族史亚组。我们还考虑了一个多基因模型，在该模型中，我们测试了家族史阳性受试者是否平均比家族史阴性受试者携带更多的精神分裂症风险等位基因。几个单独的SNPs达到提示性的，但不是全基因组的显着关联与任何家族史亚组。基于GWAS汇总统计的全基因组多基因风险评分的比较表明，与家族史阴性病例相比，家族史阳性病例中SNP效应显著富集（Nagelkerke’s R2 = 0.0021; P = 0.00331; P值阈值<0.4）。与家族史阴性的病例相比，家族史阳性的病例归因于全基因组SNPs的总效应的疾病易患性的变异性估计值显著更大（分别为0.32和0.22; P = 0.031）。我们发现了在精神分裂症的大GWAS中可检测到的等位基因效应的暗示性证据，这可能是特定家族史亚组所特有的。然而，多基因风险评分的考虑表明，常见的等位基因效应的家族史阳性病例中的显着富集。因此，正如先前的流行病学研究所表明的那样，家族性疾病可能是精神分裂症的一种更易遗传的形式。
Genome-wide association studies (GWAS) of schizophrenia have yielded more than 100 common susceptibility variants, and strongly support a substantial polygenic contribution of a large number of small allelic effects. It has been hypothesized that familial schizophrenia is largely a consequence of inherited rather than environmental factors. We investigated the extent to which familiality of schizophrenia is associated with enrichment for common risk variants detectable in a large GWAS. We analyzed single nucleotide polymorphism (SNP) data for cases reporting a family history of psychotic illness (N = 978), cases reporting no such family history (N = 4,503), and unscreened controls (N = 8,285) from the Psychiatric Genomics Consortium (PGC1) study of schizophrenia. We used a multinomial logistic regression approach with model-fitting to detect allelic effects specific to either family history subgroup. We also considered a polygenic model, in which we tested whether family history positive subjects carried more schizophrenia risk alleles than family history negative subjects, on average. Several individual SNPs attained suggestive but not genome-wide significant association with either family history subgroup. Comparison of genome-wide polygenic risk scores based on GWAS summary statistics indicated a significant enrichment for SNP effects among family history positive compared to family history negative cases (Nagelkerke’s R2 = 0.0021; P = 0.00331; P-value threshold <0.4). Estimates of variability in disease liability attributable to the aggregate effect of genome-wide SNPs were significantly greater for family history positive compared to family history negative cases (0.32 and 0.22, respectively; P = 0.031).We found suggestive evidence of allelic effects detectable in large GWAS of schizophrenia that might be specific to particular family history subgroups. However, consideration of a polygenic risk score indicated a significant enrichment among family history positive cases for common allelic effects. Familial illness might, therefore, represent a more heritable form of schizophrenia, as suggested by previous epidemiological studies.
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影响因子：
6.9
作者：
Lichtenstein, Paul;Bjork, Camilla;Sullivan, Patrick F.
通讯作者：
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影响因子：
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作者：
Ripke, Stephan;O'Dushlaine, Colm;Chambert, Kimberly;Moran, Jennifer L.;Kaehler, Anna K.;Akterin, Susanne;Bergen, Sarah E.;Collins, Ann L.;Crowley, James J.;Fromer, Menachem;Kim, Yunjung;Lee, Sang Hong;Magnusson, Patrik K. E.;Sanchez, Nick;Stahl, Eli A.;Williams, Stephanie;Wray, Naomi R.;Xia, Kai;Bettella, Francesco;Borglum, Anders D.;Bulik-Sullivan, Brendan K.;Cormican, Paul;Craddock, Nick;de Leeuw, Christiaan;Durmishi, Naser;Gill, Michael;Golimbet, Vera;Hamshere, Marian L.;Holmans, Peter;Hougaard, David M.;Kendler, Kenneth S.;Lin, Kuang;Morris, Derek W.;Mors, Ole;Mortensen, Preben B.;Neale, Benjamin M.;O'Neill, Francis A.;Owen, Michael J.;Milovancevic, Milica Pejovic;Posthuma, Danielle;Powell, John;Richards, Alexander L.;Riley, Brien P.;Ruderfer, Douglas;Rujescu, Dan;Sigurdsson, Engilbert;Silagadze, Teimuraz;Smit, August B.;Stefansson, Hreinn;Steinberg, Stacy;Suvisaari, Jaana;Tosato, Sarah;Verhage, Matthijs;Walters, James T.;Bramon, Elvira;Corvin, Aiden P.;O'Donovan, Michael C.;Stefansson, Kari;Scolnick, Edward;Purcell, Shaun;McCarroll, Steven A.;Sklar, Pamela;Hultman, Christina M.;Sullivan, Patrick F.
通讯作者：
Sullivan, Patrick F.
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DOI：
10.1176/appi.ajp.2010.09091335
发表时间：
2010-10
期刊：
The American journal of psychiatry
影响因子：
--
作者：
Huang J;Perlis RH;Lee PH;Rush AJ;Fava M;Sachs GS;Lieberman J;Hamilton SP;Sullivan P;Sklar P;Purcell S;Smoller JW
通讯作者：
Smoller JW
影响因子：
6.7
作者：
Roy, MA;Walsh, D;Kendler, KS
通讯作者：
Kendler, KS
影响因子：
3.7
作者：
Comuzzie AG;Cole SA;Laston SL;Voruganti VS;Haack K;Gibbs RA;Butte NF
通讯作者：
Butte NF