LRRTM1 on chromosome 2p12 is a maternally suppressed gene that is associated paternally with handedness and schizophrenia.
Left-right asymmetrical brain function underlies much of human cognition, behavior and emotion. Abnormalities of cerebral asymmetry are associated with schizophrenia and other neuropsychiatric disorders. The molecular, developmental and evolutionary origins of human brain asymmetry are unknown. We found significant association of a haplotype upstream of the gene LRRTM1 (Leucine-rich repeat transmembrane neuronal 1) with a quantitative measure of human handedness in a set of dyslexic siblings, when the haplotype was inherited paternally (P=0.00002). While we were unable to find this effect in an epidemiological set of twin-based sibships, we did find that the same haplotype is overtransmitted paternally to individuals with schizophrenia/schizoaffective disorder in a study of 1002 affected families (P=0.0014). We then found direct confirmatory evidence that LRRTM1 is an imprinted gene in humans that shows a variable pattern of maternal downregulation. We also showed that LRRTM1 is expressed during the development of specific forebrain structures, and thus could influence neuronal differentiation and connectivity. This is the first potential genetic influence on human handedness to be identified, and the first putative genetic effect on variability in human brain asymmetry. LRRTM1 is a candidate gene for involvement in several common neurodevelopmental disorders, and may have played a role in human cognitive and behavioral evolution.
Francks
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C
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. clyde.francks@well.ox.ac.uk
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S
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J
Abrahams
B S
BS
Velayos-Baeza
A
A
Medland
S E
SE
Colella
S
S
Groszer
M
M
McAuley
E Z
EZ
Caffrey
T M
TM
Timmusk
T
T
Pruunsild
P
P
Koppel
I
I
Lind
P A
PA
Matsumoto-Itaba
N
N
Nicod
J
J
Xiong
L
L
Joober
R
R
Enard
W
W
Krinsky
B
B
Nanba
E
E
Richardson
A J
AJ
Riley
B P
BP
Martin
N G
NG
Strittmatter
S M
SM
Möller
H-J
HJ
Rujescu
D
D
St Clair
D
D
Muglia
P
P
Roos
J L
JL
Fisher
S E
SE
Wade-Martins
R
R
Rouleau
G A
GA
Stein
J F
JF
Karayiorgou
M
M
Geschwind
D H
DH
Ragoussis
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J
Kendler
K S
KS
Airaksinen
M S
MS
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M
DeLisi
L E
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Monaco
A P
AP
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002461:Cell Line, Transformed; D002889:Chromosomes, Human, Pair 2; D005192:Family Health; D005260:Female; D007839:Functional Laterality / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D017403:In Situ Hybridization / Q000379:methods; D007621:Karyotyping; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology; D013347:Subcellular Fractions / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure
C526971:LRRTM1 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins