Gentica de las Enfermedades Mentales

Escuela de Medicina y Ciencias de la Salud

Carlos M. Restrepo, MD, PhD.
carlosmrestrepo@gmail.com
Enfermedades Mentales
Introduccin

La gentica y la genmica aplicadas a gran escala son los medios mediante los cuales se
podrn desvelar las causas genticas de la enfermedad mental. Se han identificado
genes mayores con variantes raras relacionados con enfermedad mental, pero tambin
se viene reconociendo la contribucin de pequeas variaciones comunes. En la medida
en que se entienda la contribucin de los unos y los otros ser posible entender mejor la
neurobiologa.
Hasta ahora es claro que hay una amplia heterogeneidad gentica, herencia
oligognica, polignica y compleja, que se traducen en la dificultad de entender los
mltiples niveles de circuitos, funciones moleculares y celulares, hasta la complejidad
del comportamiento humano.
Los avances actuales nos sitan en el umbral de una nueva frontera en el conocimiento
fisiopatolgico, para el diagnstico y tratamiento de la enfermedad psiquitrica.
Enfermedades Mentales
Introduccin

Se reconocen hoy causas genticas de:

Esquizofrenia (ESQ)
Desrdenes del espectro autista (AUT)
Depresin mayor (DEP)
Desorden bipolar (BIP)
Enfermedades Mentales
Introduccin

Los estudios de GWAS (estudios de asociacin de genoma

completo o genome wide association studies) de miles de
individuos, han permitido identificar las asociaciones
estadsticas de ciertos loci con alelos comunes con
frecuencias mayores al 5%.
Con GWAS se identifican variaciones de nucletido nico
que estn asociadas con el locus (gen) candidato o con otro
locus (gen) regulatorio que interviene en la funcin.

McCarthy MI, et al. Nat. Rev. Genet. 2008; 9:356369.

Maurano MT, et al. Science. 2012; 337:11901195.
ENCODE Project Consortium. Nature. 2012; 489:5774.
Enfermedades Mentales
Introduccin

Los estudios con microarrays (arrays CGH) tambin han

permitido la deteccin de mltiples variantes estructurales
raras en los cromosomas, como la variacin del nmero de
copias (CNV; con la ganancia o prdida de ADN >1 kb de
tamao) que contribuyen a una variedad de trastornos
psiquitricos, incluyendo como AUT y ESQ.

International Schizophrenia Consortium. Nature. 2008; 455:237241.

Enfermedades Mentales
Introduccin

Es hoy posible secuenciar todas las regiones del genoma

que son codificantes de protenas (Exoma). La secuenciacin
del exoma completo (whole exome sequencing) de miles de
personas ha abierto un horizonte de escala similar, con la
identificacin de mutaciones raras en los dominios
codificantes ("variantes raras con frecuencias <0,1%), que
contribuyen al riesgo de AUT y ESQ.

Iossifov I, et al. Nature. 2014; 515:216221.

Purcell SM, et al. Nature. 2014; 506:185190.
Fromer M, et al. Nature. 2014; 506:179184.
Enfermedades Mentales
Introduccin

Gemelos

100% 50%

ttps://www.google.com.co/search?q=TWINS&biw=1527&bih
https://www.cordbloodbanking.com/wp-content/uploads/2015/12/twin-babies-495x285.png
Enfermedades Mentales
Introduccin

Gentica de la esquizofrenia
Enfermedades Mentales
Genes de esquizofrenia

Correlacin genotipo-fenotipo
Cdigo OMIM Clave del Cdigo
Localizacin Fenotipo Herencia Locus Gen
Fenotipo mapeo OMIM Gen
1p36.2 {Schizophrenia 12} 181500 AD 2 SCZD12 608543
1p36.22 {Schizophrenia, susceptibility to} 181500 AD 3 MTHFR 607093
1q32.1 {Schizophrenia, susceptibility to} 181500 AD 3 CHI3L1 601525
1q42.2 {Schizoaffective disorder, susceptibility to} 181500 AD 3 DISC1 605210
1q42.2 Schizophrenia 181500 AD 2 DISC2 606271
3p25.2 {Schizophrenia, susceptibility to} 181500 AD 3 SYN2 600755
3q13.31 {Schizophrenia, susceptibility to} 181500 AD 3 DRD3 126451
5q23-q35 {Schizophrenia} 181500 AD 2 SCZD1 181510
6p23 {Schizophrenia} 181500 AD 2 SCZD3 600511
6p22.3 {Schizophrenia} 181500 AD 2 DTNBP1 607145
23 genes 6q13-q26 {Schizophrenia} 181500 AD 2 SCZD5 603175
16.04.2016 8p21 {Schizophrenia} 181500 AD 2 SCZD6 603013
10q22.3 {Schizophrenia} 181500 AD 2 SCZD11 608078
11q14-q21 {?Schizophrenia} 181500 AD 2 SCZD2 603342
12q24.11 {Schizophrenia} 181500 AD 2 DAO 124050
13q14.2 {Schizophrenia, susceptibility to} 181500 AD 3 HTR2A 182135
13q32 {Schizophrenia} 181500 AD 2 SCZD7 603176
13q33.2 {Schizophrenia} 181500 AD 2 DAOA 607408
14q32.33 {Schizophrenia, susceptibility to} 181500 AD 2 AKT1 164730
18p {Schizophrenia} 181500 AD 2 SCZD8 603206
22q11.21 {Schizophrenia, susceptibility to} 181500 AD 3 COMT 116790
22q11.21 {Schizophrenia, susceptibility to} 181500 AD 3 RTN4R 605566
22q12.3 {Schizophrenia} 181500 AD 1 APOL4 607254
22q12.3 {Schizophrenia} 181500 AD 1 APOL2 607252

http://www.omim.org/
Enfermedades Mentales
Esquizofrenia

Herencia Autosmica Dominante con Penetrancia

Incompleta

http://www.vawterlab.com/images/16.jpg
Enfermedades Mentales
Esquizofrenia

Herencia Autosmica Dominante con Penetrancia

Incompleta

The VIPR2 CNV is among the first to implicate a specific gene and neurobiological pathway in
schizophrenia. CNVs previously identified, spanning dozens of genes, were too large to yield
such clues. In the new genome-wide scan, Sebat and colleagues found the mutation in 29 of
8290 patients (.35 percent) compared to only 2 of 7431 healthy controls. A few other
schizophrenia-linked CNVs seen in previous studies were also detected.

http://www.sciencecodex.com/aggregated-images/brain/fqMnf1sH615V73bB.jpg
Enfermedades Mentales
Esquizofrenia

Herencia Autosmica Dominante con Penetrancia Incompleta

Kindred CR02 pedigree structure. Blood samples were collected from 48 members of kindred CR02, spanning three generations of this large, Mendelian-like
family. The structure exhibits unilineal transmission. Gender and structure of the pedigree were changed to protect the anonymity of participants in the
study. Individuals diagnosed with chronic schizophrenia are denoted by black symbols; black and white hatched symbols indicate schizoaffective disorder;
gray symbols represent those 'uncertain' diagnoses in which individuals were diagnosed with bipolar disorder, but also exhibited signs of personality
disorders or psychosis (included as affected in the broad diagnosis); gray hatched symbols indicate bipolar patients, not classified as affected for either
analysis. Open symbols denote unaffected individuals at the time of ascertainment. The haplotype on chromosome 5p115q13 is shared by nine of the 11
affected individuals, as indicated in the figure.
Cooper-Casey K, Msen-Fainardi A, Galke-Rollins B, Llach B, Laprade B, Rodriguez C, Riondet R, Bertheau A, Byerley W. Suggestive
linkage of schizophrenia to 5p13 in Costa Rica. Molecular Psychiatry (2005) 10, 651656.
Enfermedades Mentales
Esquizofrenia

Caso aislado, herencia multifactorial

https://www.google.com.co/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwirnLig4pbMAhUDax4KHUtgBdkQjRwIBw&u
rl=http%3A%2F%2Fwww.gwumc.edu%2Fedu%2Fobgyn%2Fgenetics%2Fcasestudies%2Fcasestudy19.html&bvm=bv.119745492,d.dmo&psig=AFQjCNFmdx
beSHIr350EAB9L4JjUb-B08Q&ust=1461020103440281
Enfermedades Mentales
Esquizofrenia

ANS ANS
ALC ALC (A) Highest lifetime (point for ASD)
DEP DEP prevalence in percentages. The
FOB FOB discontinuous bar in phobias represents
the range in different forms. (B)
CON CON Heritability estimates; bars, standard
DAH DAH error (SE). (C) SNP-based heritability
POS estimates; bars, SE. (D) Number of
POS genome-wide significant loci. The x axis
BIP BIP is discontinuous because of the large
ALI ALI difference of associated loci between
OC disorders. (E) The number of associated
OC structural variants (SVs) that either
AUT AUT reach genome-wide significance or have
ESQ ESQ been replicated with P 0.01 in another
study. (F) The y axis shows associated
TOU TOU GWAS loci (blue) and SVs (green) by
the number of cases (x axis) in the
largest study for that disorder. The
number of cases in the largest study for
GWAS (D) and SV studies (E) is
reported next to each disorder.
Abbreviations are as follows: ANX, any
anxiety disorder; AAD, alcohol abuse
ANS disorder; MDD, major depressive
ALC disorder; PHO, = any phobia; CON,
conduct disorders; PTSD, post traumatic
DEP
stress disorder; EAT, eating disorders;
FOB TS, Tourette syndrome. The order of
CON disorders and their color coding are
DAH maintained throughout the bar plots.
POS See table S1 for underlying data and
references amalgamated from many
BIP sources.
ALI
OC
AUT Geschwind DH, Flint J.
ESQ
Genetics and genomics of
TOU
psychiatric disease. Science.
2015 September 25;
349(6255): 14891494.
Enfermedades Mentales
Esquizofrenia

La heredabilidad de la esquizofrenia con base en estudios realizados con

gemelos es de aproximadamente el 78%, mientras que los basados en SNPs
muestran una heredabilidad del 58%, los estudios basados en GWAS han
mostrado una asociacin elevada del fenotipo con algunos loci genticos, con
108 loci y entre todos soportan un modelo de herencia Polignico o
Multifactorial apuntan a que la enfermedad siquitrica est asociada a variantes
comunes a un gran nmero de loci, aunque cada variante tiene slo un pequeo
efecto sobre el riesgo de la enfermedad, de acuerdo con hallazgos de otras
enfermedades comunes y complejas.
Enfermedades Mentales
Esquizofrenia

Si bien la heredabilidad por SNPs no explica todos los casos, es

probable que medien tambin variantes raras, con mayor
importancia, por lo que otros modos de herencia pueden explicar la
esquizofrenia, particularmente modelos de herencia Autosmica
Dominante.
Enfermedades Mentales
Introduccin

Gentica del autismo y los

desrdenes del espectro autista.
 Enfermedades Mentales
Genes de Autismo
Correlacin genotipo-fenotipo
Cdigo OMIM Clave del Cdigo
Localizacin Fenotipo Herencia Locus Gen
Fenotipo mapeo OMIM Gen
7q22 {Autism susceptibility 1} 209850 IC, Mu 2
13q14.2-q14.1 {Autism susceptibility 3} 608049 IC, Mu 2
15q11 {Autism susceptibility 4} 608636 AD 2
2q {Autism susceptibility 5} 606053 AR, AD 2
17q11 {Autism susceptibility 6} 609378 2
17q21 {Autism susceptibility 7} 610676 2
3q25-q27 {Autism susceptibility 8} 607373 IC, Mu 2
7q31 {Autism, susceptibility to, 9} 611015 2
7q36 {Autism, susceptibility to, 10} 611016 2
1q41-q42 {Autism susceptibility 11} 610836 2
21p13-q11 {Autism susceptibility 12} 610838 2
12q14.2 {Autism susceptibility 13} 610908 2
26 loci, 11 genes Chromosome 16p11.2 deletion syndrome, 593kb 611913 4
16p11.2
16.04.2016 {Autism susceptibility 14A} 611913 2
Chromosome 16p11.2 duplication syndrome 614671 4
16p11.2
{Autism, susceptibility to, 14B} 614671 2
7q35-q36 {Autism susceptibility 15} 612100 3 CNTNAP2 604569
3q24 ?{Autism susceptibility 16} 613410 3 SLC9A9 608396
11q13.3-q13.4 {Autism susceptibility 17} 613436 3 SHANK2 603290
14q11.2 {Autism, susceptibility to, 18} 615032 3 CHD8 610528
4q23 {Autism, susceptibility to, 19} 615091 3 EIF4E 133440
Xq13.1 {Autism susceptibility, X-linked 1} 300425 XL, IC, Mu 3 NLGN3 300336
Xp22.32-p22.31 Mental retardation, X-linked 300495 XL, IC, Mu 3 NLGN4 300427
Xp22.32-p22.31 {Autism susceptibility, X-linked 2} 300495 XL, IC, Mu 3 NLGN4 300427
Xq28 {Autism susceptibility, X-linked 3} 300496 XL, IC, Mu 3 MECP2 300005
Xp22.11 {Autism, susceptibility to, X-linked 4} 300830 XLR 3 PTCHD1 300828
Xq28 {Autism, susceptibility to, X-linked 5} 300847 3 RPL10 312173
Xq28 Epsilon-trimethyllysine hydroxylase deficiency 300872 3 TMLHE 300777

http://www.omim.org/
 Enfermedades Mentales
Genes de Autismo

http://hmg.oxf
Del16p11.2 ordjournals.org
/content/17/4/
628/F2

http://www.omim.org/
Enfermedades Mentales
Genes de Autismo
Enfermedades Mentales
Genes de Autismo

Mapeo gen
HPE8
Enfermedades Mentales
Genes de Autismo

Herencia Autosmica
Dominante con Penetrancia
Incompleta

Pedigree structure of autism spectrum disorder (ASD) families bearing the P11S variant. In total, 17 ASD families were identified to harbor the variant. Individuals
carrying the variant are marked with asterisks. Individuals for whom DNA was not available are marked as NA. Our strict analyses considered individuals as
affected if they met the criteria for autism on the Autism Diagnostic InterviewRevised (ADI-R) diagnostic algorithm (completely filled black). Our broad analyses
considered these individuals and individuals who met the criteria for ASD1 or ASD2 as affected (half filled black) (see Risi et al. 25 for details); note that no
individuals met ASD2. Unfilled individuals are considered unknown. For individuals who did not meet broad criteria, Social Responsiveness Scale (SRS), t-scores
from teacher (parent) report are provided when available. SRS scores ranging from 60 to 75 are considered mild-to-moderate range for ASD; children with high
functioning autism may score in the t-score range of 5559. AGR 804 had significant language delay and impairment as per the ADI-R, but did not meet our broad
criteria or have an SRS. Individuals with definite seizures as per the ADI-R are marked SZ=2; those with suspected seizures as per the ADI-R are marked SZ=1.

http://www.nature.com/mp/journal/v16/n1/images/mp2009118f1.jpg
Enfermedades Mentales
Genes de Autismo

Herencia Ligada al Sexo

Recesiva

Basic pedigree structure of extended autism pedigree. Affected subjects are shaded and numbered; deceased
subjects are indicated with a slash. All unaffected persons shown in this figure with an asterisk (*) were genotyped
as were all affected subjects (7 affected subjects and 22 relatives).
http://www.nature.com/mp/journal/v14/n6/fig_tab/mp200814f1.html
Enfermedades Mentales
Autismo

ANS ANS
ALC ALC (A) Highest lifetime (point for ASD)
DEP DEP prevalence in percentages. The
FOB FOB discontinuous bar in phobias represents
the range in different forms. (B)
CON CON Heritability estimates; bars, standard
DAH DAH error (SE). (C) SNP-based heritability
POS estimates; bars, SE. (D) Number of
POS genome-wide significant loci. The x axis
BIP BIP is discontinuous because of the large
ALI ALI difference of associated loci between
OC disorders. (E) The number of associated
OC structural variants (SVs) that either
AUT AUT reach genome-wide significance or have
ESQ ESQ been replicated with P 0.01 in another
study. (F) The y axis shows associated
TOU TOU GWAS loci (blue) and SVs (green) by
the number of cases (x axis) in the
largest study for that disorder. The
number of cases in the largest study for
GWAS (D) and SV studies (E) is
reported next to each disorder.
Abbreviations are as follows: ANX, any
anxiety disorder; AAD, alcohol abuse
ANS disorder; MDD, major depressive
ALC disorder; PHO, = any phobia; CON,
conduct disorders; PTSD, post traumatic
DEP
stress disorder; EAT, eating disorders;
FOB TS, Tourette syndrome. The order of
CON disorders and their color coding are
DAH maintained throughout the bar plots.
POS See table S1 for underlying data and
references amalgamated from many
BIP sources.
ALI
OC
AUT Geschwind DH, Flint J.
ESQ
Genetics and genomics of
TOU
psychiatric disease. Science.
2015 September 25;
349(6255): 14891494.
Enfermedades Mentales
Autismo

La heredabilidad del autismo es del 59% con base en estudios

realizados con gemelos, mientras que los estudios de asociacin
basados en SNPs la colocan en un 50%, los estudios de GWAS han
mostrado una menor asociacin allica con pocos loci y entre todos
soportan un modelo de herencia Polignico o Multifactorial.
Enfermedades Mentales
Autismo

Algunos casos de autismo se explican por modelos de herencia

mendeliana, Ligada al Sexo, Autosmica Dominante y otros
casos se asocian a microdeleciones o microduplicaciones
cromosmicas.
Enfermedades Mentales
Introduccin

Gentica de la depresin mayor y

el trastorno bipolar.
Enfermedades Mentales
Genes de depresin mayor y trastorno bipolar

6 genes, 16.04.2016

Correlacin genotipo-fenotipo
Cdigo Clave
Cdigo
Localizacin Fenotipo OMIM Herencia del Locus Gen
OMIM Gen
Fenotipo mapeo
{Major depressive disorder and accelerated response to
608516 3 FKBP5 602623
6p21.31 antidepressant drug treatment}
{Unipolar depression, susceptibility to} 608516 3 TPH2 607478
Major depressive disorder 1 608516 2 MDD1 608520
12q22-q23.2
{Seasonal affective disorder, susceptibility to} 608516 3 HTR2A 182135
13q14.2 {Major depressive disorder, response to citalopram therapy in} 608516 3 HTR2A 182135
15q25.3-
Major depressive disorder 2 608516 2 MDD2 608691
q26.2

http://www.omim.org/
Enfermedades Mentales
Depresin mayor y trastorno bipolar

Herencia Autosmica Dominante con Penetrancia

Incompleta

http://www.nimh.nih.gov/images/news-items/McMahonDepBipolarFamily_68763_2.jpg
Enfermedades Mentales
Depresin mayor y trastorno bipolar

ANS ANS
ALC ALC (A) Highest lifetime (point for ASD)
DEP DEP prevalence in percentages. The
FOB FOB discontinuous bar in phobias represents
the range in different forms. (B)
CON CON Heritability estimates; bars, standard
DAH DAH error (SE). (C) SNP-based heritability
POS estimates; bars, SE. (D) Number of
POS genome-wide significant loci. The x axis
BIP BIP is discontinuous because of the large
ALI ALI difference of associated loci between
OC disorders. (E) The number of associated
OC structural variants (SVs) that either
AUT AUT reach genome-wide significance or have
ESQ ESQ been replicated with P 0.01 in another
study. (F) The y axis shows associated
TOU TOU GWAS loci (blue) and SVs (green) by
the number of cases (x axis) in the
largest study for that disorder. The
number of cases in the largest study for
GWAS (D) and SV studies (E) is
reported next to each disorder.
Abbreviations are as follows: ANX, any
anxiety disorder; AAD, alcohol abuse
ANS disorder; MDD, major depressive
ALC disorder; PHO, = any phobia; CON,
conduct disorders; PTSD, post traumatic
DEP
stress disorder; EAT, eating disorders;
FOB TS, Tourette syndrome. The order of
CON disorders and their color coding are
DAH maintained throughout the bar plots.
POS See table S1 for underlying data and
references amalgamated from many
BIP sources.
ALI
OC
AUT Geschwind DH, Flint J.
ESQ
Genetics and genomics of
TOU
psychiatric disease. Science.
2015 September 25;
349(6255): 14891494.
Enfermedades Mentales
Depresin mayor y trastorno bipolar

La heredabilidad de la depresin mayor y el trastorno bipolar es del

60 y 50% respectivamente; los estudios de asociacin basados en
SNPs la colocan en un 30%, los estudios de GWAS han mostrado una
menor asociacin allica con 10 a 100 loci candidatos y todos
soportan un modelo de herencia Polignica o Multifactorial.
Enfermedades Mentales
Depresin mayor y trastorno bipolar

Algunos casos de Depresin Mayor y Trastorno Bipolar se

explican por modelos de herencia mendeliana Autosmica
Dominante.
Enfermedades Mentales
Introduccin

Otros tipos de enfermedades

mentales.
Enfermedades Mentales
Otras enfermedades mentales

ANS ANS
ALC ALC (A) Highest lifetime (point for ASD)
DEP DEP prevalence in percentages. The
FOB FOB discontinuous bar in phobias represents
the range in different forms. (B)
CON CON Heritability estimates; bars, standard
DAH DAH error (SE). (C) SNP-based heritability
POS estimates; bars, SE. (D) Number of
POS genome-wide significant loci. The x axis
BIP BIP is discontinuous because of the large
ALI ALI difference of associated loci between
OC disorders. (E) The number of associated
OC structural variants (SVs) that either
AUT AUT reach genome-wide significance or have
ESQ ESQ been replicated with P 0.01 in another
study. (F) The y axis shows associated
TOU TOU GWAS loci (blue) and SVs (green) by
the number of cases (x axis) in the
largest study for that disorder. The
number of cases in the largest study for
GWAS (D) and SV studies (E) is
reported next to each disorder.
Abbreviations are as follows: ANX, any
anxiety disorder; AAD, alcohol abuse
ANS disorder; MDD, major depressive
ALC disorder; PHO, = any phobia; CON,
conduct disorders; PTSD, post traumatic
DEP
stress disorder; EAT, eating disorders;
FOB TS, Tourette syndrome. The order of
CON disorders and their color coding are
DAH maintained throughout the bar plots.
POS See table S1 for underlying data and
references amalgamated from many
BIP sources.
ALI
OC
AUT Geschwind DH, Flint J.
ESQ
Genetics and genomics of
TOU
psychiatric disease. Science.
2015 September 25;
349(6255): 14891494.
Enfermedades Mentales
Correlacin gentica entre pares de enfermedades

(Plotted on the vertical axis are

BPD, SCZ, MDD, and ASD (2). The
horizontal colored lines mark the
mean of the genetic correlation
based on SNP sharing for each
pair of illnesses, and the dotted
vertical colored lines are the SEs of
the estimates. Data are from
Maier et al. (69).

BIP/ESQ DEP/ESQ DEP/BIP AUT/ESQ AUT/BIP AUT/DEP Geschwind DH, Flint J.

Genetics and genomics of
psychiatric disease. Science.
2015 September 25;
349(6255): 14891494.
Enfermedades Mentales
Introduccin

Clinical disorders and their

overlap, represented by the big
circles. The smaller dots within
each circle represent contributing
genetic or environmental risk
factors. Once genetic risk is
defined in population studies, it
DAH AUT ESQ BIP DEP ALC
can be used to define factors
underlying disease risk in
individuals, identifying distinct (or
overlapping) entities, two of
which are represented by the
elongated ovals at the bottom,
grounded in causal mechanistic
understanding. These subtypes
should more clearly inform
prognosis and treatment than do
current categorical disease
entities. The sizes of the dots
within the circles represent the
relative effect sizes of variants.

Geschwind DH, Flint J.

Genetics and genomics of
psychiatric disease. Science.
2015 September 25;
349(6255): 14891494.
Enfermedades Mentales
Genes y variantes con efecto en el autismo

Heterogeneous genetic risk

factors converge in biological
networks. Different study
designs, such as trios, multiplex
affected families, or case-control
(shown at far left) identify
different forms of genetic risk in
cases (the arrow size indicates
the relative effect size). By
integrating these data with
biological network data, one can
assess in a genome-wide
manner whether disease-
Autismo associated risk variants are
enriched in specific biological
networks. Here, for illustration,
we depict rare de novo variants
associated with ASD, enriched in
the yellow module. The function
of this module of co-regulated
genes can be further annotated
using gene ontology, which
implicates these large-effect
ASD-associated variants in
chromatin remodeling,
transcriptional regulation, and
neurogenesis. Networks can be
subsequently mapped onto
Interactoma developmental time points,
brain regions, circuits, or cells.

Geschwind DH, Flint J. Genetics and genomics of psychiatric disease. Science. 2015 September 25; 349(6255): 14891494.
Enfermedades Mentales
Gentica de las enfermedades mentales

Herencia mendeliana (mutacin mayor)

Herencia cromosmica (enfermedad de genes contiguos)
Herencia compleja (mltiples variantes con efecto aditivo)

Paneles multignicos para enfermedades mendelianas

CGH (hibridacin genmica comparativa) en autismo
Anlisis complejos de expresin de muchos genes y sus
variantes.
Enfermedades Mentales
Gentica de las enfermedades mentales

Riesgo de recurrencia:
Autosmica dominante 50%
Autosmica recesiva 25%
Ligada al sexo recesiva 50%
Herencia compleja 5-10%
Enfermedades Mentales
Conclusin

Estos avances todava no ofrecen una imagen completa de la

arquitectura gentica necesaria para entender las enfermedades
mentales, dado que sera necesario tambin identificar
variaciones de secuencia que causen cambios menores en las
protenas, fenmenos de epistasis, herencia oligognica y
compleja. No obstante, es claro que si hay un componente
gentico de base en las enfermedades mentales, pero no est
suficiente entendido para tener conclusiones.

Iossifov I, et al. Nature. 2014; 515:216221.

Purcell SM, et al. Nature. 2014; 506:185190.
Fromer M, et al. Nature. 2014; 506:179184.
Enfermedades Mentales
Conclusin

..los hallazgos genticos desdibujan las fronteras no slo

de enfermedades psiquitricas, sino tambin los lmites
entre el estado de enfermedad y la variacin normal en la
medida que se identifican genes de riesgo .........."

Geschwind DH, Flint J. Genetics and genomics of psychiatric disease.

Science. 2015 September 25; 349(6255): 14891494.