Directional dominance on stature and cognition in diverse human populations.
Directional dominance on stature and cognition in diverse human populations.
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DOI：
10.1038/nature14618
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发表时间：
2015-07-23
期刊：
影响因子：
64.8
通讯作者：
Wilson JF
中科院分区：
文献类型：
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作者：
Joshi PK;Esko T;Mattsson H;Eklund N;Gandin I;Nutile T;Jackson AU;Schurmann C;Smith AV;Zhang W;Okada Y;Stančáková A;Faul JD;Zhao W;Bartz TM;Concas MP;Franceschini N;Enroth S;Vitart V;Trompet S;Guo X;Chasman DI;O'Connel JR;Corre T;Nongmaithem SS;Chen Y;Mangino M;Ruggiero D;Traglia M;Farmaki AE;Kacprowski T;Bjonnes A;van der Spek A;Wu Y;Giri AK;Yanek LR;Wang L;Hofer E;Rietveld CA;McLeod O;Cornelis MC;Pattaro C;Verweij N;Baumbach C;Abdellaoui A;Warren HR;Vuckovic D;Mei H;Bouchard C;Perry JRB;Cappellani S;Mirza SS;Benton MC;Broeckel U;Medland SE;Lind PA;Malerba G;Drong A;Yengo L;Bielak LF;Zhi D;van der Most PJ;Shriner D;Mägi R;Hemani G;Karaderi T;Wang Z;Liu T;Demuth I;Zhao JH;Meng W;Lataniotis L;van der Laan SW;Bradfield JP;Wood AR;Bonnefond A;Ahluwalia TS;Hall LM;Salvi E;Yazar S;Carstensen L;de Haan HG;Abney M;Afzal U;Allison MA;Amin N;Asselbergs FW;Bakker SJL;Barr RG;Baumeister SE;Benjamin DJ;Bergmann S;Boerwinkle E;Bottinger EP;Campbell A;Chakravarti A;Chan Y;Chanock SJ;Chen C;Chen YI;Collins FS;Connell J;Correa A;Cupples LA;Smith GD;Davies G;Dörr M;Ehret G;Ellis SB;Feenstra B;Feitosa MF;Ford I;Fox CS;Frayling TM;Friedrich N;Geller F;Scotland G;Gillham-Nasenya I;Gottesman O;Graff M;Grodstein F;Gu C;Haley C;Hammond CJ;Harris SE;Harris TB;Hastie ND;Heard-Costa NL;Heikkilä K;Hocking LJ;Homuth G;Hottenga JJ;Huang J;Huffman JE;Hysi PG;Ikram MA;Ingelsson E;Joensuu A;Johansson Å;Jousilahti P;Jukema JW;Kähönen M;Kamatani Y;Kanoni S;Kerr SM;Khan NM;Koellinger P;Koistinen HA;Kooner MK;Kubo M;Kuusisto J;Lahti J;Launer LJ;Lea RA;Lehne B;Lehtimäki T;Liewald DCM;Lind L;Loh M;Lokki ML;London SJ;Loomis SJ;Loukola A;Lu Y;Lumley T;Lundqvist A;Männistö S;Marques-Vidal P;Masciullo C;Matchan A;Mathias RA;Matsuda K;Meigs JB;Meisinger C;Meitinger T;Menni C;Mentch FD;Mihailov E;Milani L;Montasser ME;Montgomery GW;Morrison A;Myers RH;Nadukuru R;Navarro P;Nelis M;Nieminen MS;Nolte IM;O'Connor GT;Ogunniyi A;Padmanabhan S;Palmas WR;Pankow JS;Patarcic I;Pavani F;Peyser PA;Pietilainen K;Poulter N;Prokopenko I;Ralhan S;Redmond P;Rich SS;Rissanen H;Robino A;Rose LM;Rose R;Sala C;Salako B;Salomaa V;Sarin AP;Saxena R;Schmidt H;Scott LJ;Scott WR;Sennblad B;Seshadri S;Sever P;Shrestha S;Smith BH;Smith JA;Soranzo N;Sotoodehnia N;Southam L;Stanton AV;Stathopoulou MG;Strauch K;Strawbridge RJ;Suderman MJ;Tandon N;Tang ST;Taylor KD;Tayo BO;Töglhofer AM;Tomaszewski M;Tšernikova N;Tuomilehto J;Uitterlinden AG;Vaidya D;van Hylckama Vlieg A;van Setten J;Vasankari T;Vedantam S;Vlachopoulou E;Vozzi D;Vuoksimaa E;Waldenberger M;Ware EB;Wentworth-Shields W;Whitfield JB;Wild S;Willemsen G;Yajnik CS;Yao J;Zaza G;Zhu X;Project TBJ;Salem RM;Melbye M;Bisgaard H;Samani NJ;Cusi D;Mackey DA;Cooper RS;Froguel P;Pasterkamp G;Grant SFA;Hakonarson H;Ferrucci L;Scott RA;Morris AD;Palmer CNA;Dedoussis G;Deloukas P;Bertram L;Lindenberger U;Berndt SI;Lindgren CM;Timpson NJ;Tönjes A;Munroe PB;Sørensen TIA;Rotimi CN;Arnett DK;Oldehinkel AJ;Kardia SLR;Balkau B;Gambaro G;Morris AP;Eriksson JG;Wright MJ;Martin NG;Hunt SC;Starr JM;Deary IJ;Griffiths LR;Tiemeier H;Pirastu N;Kaprio J;Wareham NJ;Pérusse L;Wilson JG;Girotto G;Caulfield MJ;Raitakari O;Boomsma DI;Gieger C;van der Harst P;Hicks AA;Kraft P;Sinisalo J;Knekt P;Johannesson M;Magnusson PKE;Hamsten A;Schmidt R;Borecki IB;Vartiainen E;Becker DM;Bharadwaj D;Mohlke KL;Boehnke M;van Duijn CM;Sanghera DK;Teumer A;Zeggini E;Metspalu A;Gasparini P;Ulivi S;Ober C;Toniolo D;Rudan I;Porteous DJ;Ciullo M;Spector TD;Hayward C;Dupuis J;Loos RJF;Wright AF;Chandak GR;Vollenweider P;Shuldiner A;Ridker PM;Rotter JI;Sattar N;Gyllensten U;North KE;Pirastu M;Psaty BM;Weir DR;Laakso M;Gudnason V;Takahashi A;Chambers JC;Kooner JS;Strachan DP;Campbell H;Hirschhorn JN;Perola M;Polašek O;Wilson JF
纯合性长期以来一直与罕见的，往往是毁灭性的，孟德尔疾病和达尔文是第一个认识到，近亲繁殖减少进化的适应性。然而，现代人群中常见的更远的父母关系的影响还不太清楚。基因组数据现在允许我们通过观察连续的纯合片段（纯合性运行，ROH）来研究纯合性对公共卫生重要性性状的影响，这些片段被推断为沿其全长沿着是纯合的。鉴于在大多数人群中普遍存在低水平的全基因组纯合性，需要大量人群的信息才能提供足够的效力。在这里，我们使用ROH研究了来自102个队列的354，224名个体的16个健康相关的数量性状，并发现纯合性总和（SROH）与四个复杂性状之间存在统计学显著相关性：身高、1秒用力呼气肺容积（FEV1）、一般认知能力（g）和教育程度（标称p<1 × 10−300、2.1 × 10−6、2.5 × 10−10、1.8 × 10−10）。在每一种情况下，增加纯合性与减少性状值，相当于后代的第一堂兄弟是1.2厘米短，有10个月的教育。在四个大陆群体和具有不同程度全基因组纯合性的人群中发现了类似的效应大小，首次提供了令人信服的证据，证明纯合性而不是混淆直接影响表型方差。与早期在小样本中的报道相反，没有证据表明全基因组纯合性对血压和低密度脂蛋白（LDL）胆固醇或其他10种心脏代谢性状的影响。由于定向显性预测性状的定向进化选择，这项研究提供了证据，增加身高和认知功能已被积极选择在人类进化，而晚发型复杂疾病的许多重要的危险因素可能没有。
Homozygosity has long been associated with rare, often devastating, Mendelian disorders and Darwin was one of the first to recognise that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity, ROH), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use ROH to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts and find statistically significant associations between summed runs of homozygosity (SROH) and four complex traits: height, forced expiratory lung volume in 1 second (FEV1), general cognitive ability (g) and educational attainment (nominal p<1 × 10−300, 2.1 × 10−6, 2.5 × 10−10, 1.8 × 10−10). In each case increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing convincing evidence for the first time that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein (LDL) cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.