Genetic Epidemiology, Psychiatric Genetics, Asthma Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
26131930
TITLE
Directional dominance on stature and cognition in diverse human populations.
ABSTRACT
Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is 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), 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 runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). 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 evidence 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 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.
DATE PUBLISHED
2015 Jul 23
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2015/02/01
accepted 2015/05/28
aheadofprint 2015/07/01
entrez 2015/07/02 06:00
pubmed 2015/07/02 06:00
medline 2015/08/08 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Joshi PK
Esko T
Mattsson H
Eklund N
Gandin I
Nutile T
Jackson AU
Schurmann C
Smith AV
Zhang W
Okada Y
Stancakova 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 JR
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
Magi 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 SJ
Barr RG
Baumeister SE
Benjamin DJ
Bergmann S
Boerwinkle E
Bottinger EP
Campbell A
Chakravarti A
Chan Y
Chanock SJ
Chen C
Chen YD
Collins FS
Connell J
Correa A
Cupples LA
Smith GD
Davies G
Dorr 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
Heikkila K
Hocking LJ
Homuth G
Hottenga JJ
Huang J
Huffman JE
Hysi PG
Ikram MA
Ingelsson E
Joensuu A
Johansson A
Jousilahti P
Jukema JW
Kahonen 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
Lehtimaki T
Liewald DC
Lind L
Loh M
Lokki ML
London SJ
Loomis SJ
Loukola A
Lu Y
Lumley T
Lundqvist A
Mannisto 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
Toglhofer AM
Tomaszewski M
Tsernikova 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
BioBank Japan Project
Salem RM
Melbye M
Bisgaard H
Samani NJ
Cusi D
Mackey DA
Cooper RS
Froguel P
Pasterkamp G
Grant SF
Hakonarson H
Ferrucci L
Scott RA
Morris AD
Palmer CN
Dedoussis G
Deloukas P
Bertram L
Lindenberger U
Berndt SI
Lindgren CM
Timpson NJ
Tonjes A
Munroe PB
Sorensen TI
Rotimi CN
Arnett DK
Oldehinkel AJ
Kardia SL
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
Perusse 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 PK
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 RJ
Wright AF
Chandak GR
Vollenweider P
Shuldiner AR
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
Polasek O
Wilson JF
INVESTIGATORS
JOURNAL
VOLUME: 523
ISSUE: 7561
TITLE: Nature
ISOABBREVIATION: Nature
YEAR: 2015
MONTH: Jul
DAY: 23
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1476-4687
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Nature
COUNTRY: England
ISSNLINKING: 0028-0836
NLMUNIQUEID: 0410462
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Meta-Analysis
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GRANTID AGENCY COUNTRY
068545 Wellcome Trust United Kingdom
072856 Wellcome Trust United Kingdom
072960 Wellcome Trust United Kingdom
079771 Wellcome Trust United Kingdom
084723 Wellcome Trust United Kingdom
098051 Wellcome Trust United Kingdom
099194 Wellcome Trust United Kingdom
105022 Wellcome Trust United Kingdom
250157 European Research Council International
280559 European Research Council International
323195 European Research Council International
BARCVBRU-2012-1 Department of Health United Kingdom
BB/F019394/1 Biotechnology and Biological Sciences Research Council United Kingdom
CZB/4/276 Chief Scientist Office United Kingdom
CZB/4/505 Chief Scientist Office United Kingdom
CZB/4/710 Chief Scientist Office United Kingdom
CZD/16/6 Chief Scientist Office United Kingdom
CZD/16/6/2 Chief Scientist Office United Kingdom
CZD/16/6/3 Chief Scientist Office United Kingdom
CZD/16/6/4 Chief Scientist Office United Kingdom
ETM/55 Chief Scientist Office United Kingdom
G0601966 Medical Research Council United Kingdom
G0700704 Medical Research Council United Kingdom
G0700931 Medical Research Council United Kingdom
G0701863 Medical Research Council United Kingdom
G9521010 Medical Research Council United Kingdom
G9815508 Medical Research Council United Kingdom
K24 DK080140 NIDDK NIH HHS United States
MC_PC_U127561128 Medical Research Council United Kingdom
MC_U106179471 Medical Research Council United Kingdom
MC_U127561128 Medical Research Council United Kingdom
MC_UU_12013/3 Medical Research Council United Kingdom
MC_UU_12015/1 Medical Research Council United Kingdom
MR/K026992/1 Medical Research Council United Kingdom
P20 MD006899 NIMHD NIH HHS United States
P30 DK020572 NIDDK NIH HHS United States
P30 DK063491 NIDDK NIH HHS United States
R01 AG033193 NIA NIH HHS United States
R01 DK072193 NIDDK NIH HHS United States
R01 DK078616 NIDDK NIH HHS United States
R03 DC013373 NIDCD NIH HHS United States
RG/2001004/12869 British Heart Foundation United Kingdom
RP-PG-0407-10371 Department of Health United Kingdom
SAG09977 Biotechnology and Biological Sciences Research Council United Kingdom
SRF/01/010 Department of Health United Kingdom
U01 AG049505 NIA NIH HHS United States
U01 DK062370 NIDDK NIH HHS United States
U01 DK078616 NIDDK NIH HHS United States
UL1 TR000124 NCATS NIH HHS United States
Medical Research Council United Kingdom
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Biological Evolution
Blood Pressure genetics
Body Height genetics
Cholesterol, LDL genetics
Cognition genetics
Cohort Studies genetics
Educational Status genetics
Female genetics
Forced Expiratory Volume genetics
Genome, Human genetics
Homozygote genetics
Humans genetics
Lung Volume Measurements genetics
Male genetics
Phenotype genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 Cholesterol, LDL
OTHER ID's
OTHERID SOURCE
EMS63641 NLM
PMC4516141 NLM