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Guide to detecting genetic vulnerability for bipolar I disorder in the Romanian


population

Author: Maria Grigoroiu-Serbanescu

Psychiatric Genetics Research Unit


Alexandru Obregia Clinical Psychiatric Hospital
Bucharest, Romania

Durinng the performance of the research project “Genome-wide study of bipolar I disorder
and guide for assessing the genetic risk for bipolar I disorder in the Romanian population” (grant
no. 89/ 2012 funded by UEFISCDI, Romania) we developed several investigation directions for
estimating the genetic risk of bipolar disorder (BP) and other major psychiatric disorders in first
degree relatives of BP patients: a) the molecular direction ( candidate gene and genome-wide
association studies (GWAS)); b) clinical genetic epidemiology (recurrence or morbid risk (MR) for
BP-I and for all major psychoses (BP-I, BP-II, recurrent unipolar major depression, schizoaffective
disorders, and schizophrenia) .
We add to this guide a third direction followed in previous research projects, namely c) the
developmental psychopathology direction (precursors of BP and subclinical psychopathology in
offspring of BP patients). This allows to families and psychiatry professionals to indentify early
illness signs and take adequate therapeutic measures.
BP disorder is a polygenic disorder that involves genetic, epigenetic, and possibly
immunologic mechanisms not well understood at the current knowledge state. Although its
biometric heritability based on family and twin studies is high (around 80%) (Barnett & Smoller,
2009), the SNP-based heritability is very low.
The genetic contribution to the liability for major psychoses is around 80% for bipolar
disorder (BP) and schizophrenia (SCZ) (Lichtenstein et al, Lancet, 2009) and 48%-75% for unipolar
major depression (Mdd-UP) (McGuffin et al, Archives of General Psychiatry, 1996), the
environment being responsible for the rest of the variance. The genetic component is expressed in
the familial risk for mental disorders.
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Several studies showed that first degree relatives of both BP and SCZ patients have risk to develop
both disorders and additionally, they are at high risk for Mdd-UP. This epidemiologic finding is
supported by molecular studies showing high overlapping genetic basis for major psychoses (Cross-
Disorder Group of PGC, Lancet, 2013).

From Cross Disorder


Group of PGC. The
Lancet, 2013

I. Molecular basis of BP in the Romanian population


We investigated the molecular basis of the BP-I disorder (disorder characterized by
alternating manic/ mixed mood episodes and depressive episodes that hamper the social and
professional functioning of the individual) using two strategies: a) the candidate gene strategy; b)
the genome wide association strategy at gene level and microRNA level. These strategies led to the
discovery of new genes associated with BP or to replication in the Romanian population of genes
discovered in large scale multinational samples. Replication of genes in a population is necessary
because the genetic structure of different populations is heterogeneous and a gene/ polymorphism
(SNP) associated with a trait/disorder in a population is not necessarily associated with the same
trait/ disorder in another population or does not show the same effect direction (risk or protective).
In Table 1 we summarized 34 genes/45 SNPs found associated with the BP-I in the Romani
an population. Table 1 indicates the gene/SNP nane and location, polymorphism (Allele 1/Allele 2 t
he associated and the risk allele in the Romanian population, effect size (odds ratio = OR and associ
ation significance level = P), study type (discovery or replication), associated phenotype/ subphenot
ype, and the expression in the human brain when available. Other 19 genes were found associated
with the BP in the Romanian population in the Psychiatric Genomics Consortium (PGC) genome-wi
de analysis carried out on a multinational sample that included our sample too. But we cannot report
these genes since they were not published yet.
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Table nr. 1. Genes conferring risk for bipolar disorder in the Romanian population

Gene/ SNP/ Risk allele OR / P Study type/ Associated Expression in


Chromosome A1/A2 Reference phenotype/ humans
subphenotype
1. TRANK1/ LBA1 rs9834970 Risk = C OR = 1.24; Replication/ Global BP; early onset Frontal cortex ,
intergenic (C/T) P = 0.024 ( Grigoroiu-Serbanescu et al, 2015; BP-I (OR = 1.33; P = prefrontal cortex,
3p22.2 Pgw =4.83E−10 Hou et al, HMG, 2016) 0.013) cerebellum
2.MAD1L1 rs11764590 Risk = T OR = 1.28; Discovery / replication Global BP Hippocampus;
(mitotic arrest intronic (Cichon et al, 2011;Grigoroiu- cortex
deficient-like 1) (T/C) P = 0.019 Serbanescu et al, 2015)
7p22.3
MAD1L1 rs4236274 Assoc = G OR = 0.87 Replication/ Global BP Hippocampus;
(G/A) Risk = A P = 8.49E-12 (Hou et al, HMG, 2016) cortex
7p22.3
3.NCAN rs1064395 Risk = A OR = 1.38 Discovery/ Global BP; late onset Hippocampus
(Neurocan) (3’UTR) P = 0.048 replication (Cichon et a al, 2011; BP
19p13.11 (A/G) Pgw=3.36E- Grigoroiu-Serbanescu et al, 2015; (OR = 1.31; P = 0.05)
OR = 1.11 Hou et al, HMG, 2016)
4.TRPC4AP rs3818253 Assoc = A OR = 0.77 Replication/ Late onset BP
intronic Risk = G (Grigoroiu-Serbanescu et al,
20 (A/G) P = 0.025 2015)
TRPC4AP/ MYH7B/ rs6088662 Risk = G OR = 1.04 Replication/ BP; SCZ; cognitive Hippocampal
GGT7 (G/T) P = 3.54x10-8 (Li et al, BJP, 2016 ) functions volume;
20q11.22
5. MYO5B rs4939921 Assoc= G OR = 0.70 Replication/ Late onset BP
intronic Risk = A (Grigoroiu-Serbanescu et al, 2015)
18 (G/A) P = 0.026
6. EGFR rs729969 Risk = T OR = 1.39 Replication/ Late onset BP Brain
(epidermal growth intronic (T/C) (Grigoroiu-Serbanescu et al, 2015)
factor receptor) P = 0.015
7p11.2
EGFR rs17172438 Risk = C OR = 1.45 Replication/ Late onset BP
intronic (C/T) (Grigoroiu-Serbanescu et al, 2015)
7p11.2 P = 0.00081
7. Nearst MMP16 rs7004633 Risk = G OR = 1.41 Replication/ Global BP ; Early
(G/A) (Grigoroiu-Serbanescu et al, 2015) onset BP
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8q21.3 P = 0.005
8. AS3MT rs11191454 Risk = A OR = 1.68 Replication/ Late onset BP
10q24.32 intronic (A/G) P = 0.007 (Grigoroiu-Serbanescu et al, 2015)
9 .CACNA1C rs4765913 Assoc = A OR = 0.80 Replication/ Global BP; late onset
(A/T) Risk = T P = 0.058 (Grigoroiu-Serbanescu et al, 2015) BP-I
12p13
10. CNNM2 rs7914558 Risk = G OR = 1.25 Replication/ Late onset BP-I
intragenic (G/A) P = 0.052 (Grigoroiu-Serbanescu et al, 2015)
10q24.32
11. NT5C2 rs11191580 Risk = T OR = 1.62 Replication / Late onset BP-I
intragenic (T/C) P = 0.015 (Grigoroiu-Serbanescu et al, 2015)
10q24.33
12. CSMD1 rs10503253 Risk = A OR = 1.28 Replication/
intragenic (A/C) P =0.074 (Grigoroiu-Serbanescu et al, 2015) Late onset BP-I
8p23.2
13. PBRM1 rs2251219 Risk = C OR = 1.18 Replication/ Global BP
(Polybromo1) synonimous P = 0.003 (Vassos et al, 2012)
3p21.1 (C/T) Pgw=2.68x10-9
14. CSMD2 rs9662615 Assoc= T P = 5.26E-7* Discovery/ Lithium response
1 (T/C) (Hou et al, Lancet, 2016)
CSMD2 rs771148 Assoc = C P = 7.·01E-7* Discovery/ Lithium response
1 (C/T) (Hou et al, Lancet, 2016)
15. HDAC9 rs61549860 Associ = T P = 5.44E-7* Discovery Lithium response
(T/A) Hou et al, Lancet, 2016
7
16. AL157359.4 rs79663003 Assoc = T P =1.30E-8* Discovery/ Lithium response
(T/C) Hou et al, Lancet, 2016
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AL157359.4 rs78015114 Assoc = T P = 1.25E-8* Discovery/ Lithium response
(T/C) Hou et al, Lancet, 2016
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17. AL157359.3 rs74795342 Assoc = G P = 3.00E-9* Discovery/ Lithium response
(G/A) Hou et al, Lancet, 2016
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AL157359.3 rs75222709 Assoc = T P = 3.14E-9* Discovery/ Lithium response
(T/G) Hou et al, Lancet, 2016
21
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18. ADCY2 rs17826816 Risk = G OR = 1.14 Discovery Global BP Brain


(G/A) P = 9.9 x10-9* (Muehleisen et al, 2014)
5p15.31
19. MIR2113 / rs12202969 Risk = A OR = 1.12 Discovery Global BP Neocortex
POU3F2 intergenic P = 1.08 x10-8* (Muehleisen et al, 2014) development
6q16.1 (A/G)
MIR2113/ rs1487441 Risk = A OR = 1.12 Discovery Global BP Encodes dendrin;
POU3F2 intergenic P= 2.58E-08 (Hou et al, HMG, 2016) expressed synapses
6q16.1 ( A/G)
20.HTR3Bp.Y129S rs1176744 Assoc = OR = 0.88 Replication/ Global BP; male sex
(serotonin receptor (A/C) p.129S P = 0.009* (Hammer et al, 2012) specific ( OR = 0.79;
3B) (protective) P = 0.0002 )
Risk =p.129Y
21. ELAVL2 rs12553324 Risk = G OR = 1.12 Discovery/ Global BP Promotes neural
intergenic (G/C) P = 5.87E-09 (Hou et al, HMG, 2016) development
9p21.3 non-synonimous
22. DDN (3’-UTR) rs1054442 Risk = C OR =1.13 Discovery/ Global BP Encodes dendrin
(C/A) P = 1.20E-08 (Hou et al, HMG, 2016) (synaptic protein);
12q31.1 expressed in skeletal
muscle tissue
23. ERBB2 rs2517959 Risk = A OR = 1.13 Dicovery/ Global BP Brain, neural tissue
intronic P = 4.53E-09 (Hou et al, HMG, 2016)
17q12 (A/T)
24. LRP8 rs5174 (C/T) Risk = C OR=1.12 Dicovery/ Global BP; SCZ; Brain (amygdala,
(low-density lipoprotein exon 9, non- Pgw = 2.64×10−4 (Li et al, Mol Neurobiol, 2016) psychosis (Hippocampus,
receptor-related protein8 synonimous cerebellum)
1p32.3
25. PCDH17 rs9537793 Risk = G OR = 1.17 Discovery/ Global BP; unipolar cortical neurons;
(Protocadherin 17) (G/A) Pgw = 0.044 (Li et al, , Mol Psychiatry, 2016) major depression reduced amygdala
13q21.1 volume
26. CHDH rs9836592 Risk = T OR = 1.22 Discovery/ Global BP hippocampus ,
(C/T) (Chang et al, 2016) cingulate cortex,
3p21.1 Pgw = 0.055 cerebellar
hemispheres
27. miR-499 rs3818253 Target genes: OR = 1.38 Discovery/ Global BP brain
ENAH, VAV3, (Forstner et al, 2015)
20 PFN2 P = 0.0012
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28. miR-708 rs7108878 Target genes: OR = 1.35 Discovery/ Global BP brain


ATXN1, (Forstner et al, 2015)
11 SHANK3, 2.85 x 10-5
PFKM,
FOXN3 P = 0.0012

29. miR-1908 Target genes: Discovery/ brain


PCDHA11,PC
11 DHA1 P = 2.85 x 10-5 (Forstner et al, 2015)
rs174575 PCDHA9, Global BP
PCDHA5, P = 0.0353
PCDHA3,
PCDHA8
30. ANK3 rs9804190 Risk = T OR =1.68 Replication/ (Grigoroiu-Serbanescu Late onset BP
et al, 2015)
10q21.2 (C/T) P = 0.035

31. PALB2 rs420259 Risk = G OR = 1.47 Replication / Late onset BP-I


(G/A) P = 0.043 (Grigoroiu-Serbanescu et al, 2015)
16p12.2
32. CACNA1C rs4765905 Risk = C OR = 1.43 Replication / Late onset BP-I
(C/G) P = 0.051 (Grigoroiu-Serbanescu et al, 2015)
12p13
CACNA1C rs4765913 Risk = T OR = 1.12 Replication/ Global BP-I, late onset
BP
12p13 (A/T) P = 9.87E-10/ (Grigoroiu-Serbanescu et al, 2015)
0.058

33. G72/G30 rs3916965 (M12) Risk = G OR = 1.82 Replication/ (Grigoroiu-Serbanescu Non-psychotic


(G/A) intergenic et al, 2010)
P = 0.044 BP-I
12q24
33. G72/G30 rs1935057 (A/G) Risk = A OR = 1.88 Replication/ (Grigoroiu-Serbanescu Non-psychotic BP-I
intergenic et al, 2010)
P = 0.037
12q24
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33. G72/G30 rs3916967 (M14) Risk = A OR = 1.82 Replication/ (Grigoroiu-Serbanescu Non-psychotic BP-I
(A/G) Upstream et al, 2010)
P = 0.043
12q24 5′UTR

33. G72/G30 rs2391191 (M15) Risk = G OR = 1.82 Replication / (Grigoroiu- Non-psychotic BP-I
(G/A) Non- Serbanescu et al, 2010)
P = 0.043
12q24 synony-mous
coding Lys30Arg
34. TPH2 Haplotype Risk=ACCA; OR = 1.93 Replication/ discovery Global BP-I, familial
rs1386497, cases, early onset BP-I;
12q21 ACCG P = 0.0096/ (Grigoroiu-Serbanescu et al, 2008) paternal transmission
rs11834097,
rs4760820,
P = 0.01
rs17722134

19 new genes discovered together with PGC will be mentioned after publication.

Legend : SCZ = schizophrenia; Pgw = P-genome-wide; early onset = age of onset < 25; late onset = age of onset ≥ 25;
assoc = associated
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Further we present some results on genes/ SNPs discovered/ replicated in the Romanian
population in comparison with other populations of European ancestry in the collaborative
studies we were involved during the performance of the current project. The forest plots of different
samples illustrate the genetic heterogeneity of European populations and the necessity of replication
studies.

Comparison between the Romanian BP-I patient and control samples and other BP and control s
amples of European ancestry for some newly discovered or replicated genes

1) NCAN gene (from Cichon et al, 2011)


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2) CHDH gene first discovered in the Romanian sample (From Chang et al, Molecular
Neurobiology, 2016)

Figure 2. Forest plot of odds ratios


with 95% confidence interval for
BPD samples included in meta-
analysis of rs9836592 (CHDH gene).
(Chang et al, 2016, Mol
Neurobiology)

Figure 1. Genetic association of CHDH


with risk for BPD. A physical map of the
region is given and depicts known genes
within the region. Bottom, the linkage
disequilibrium structure of the tested
markers for 490 unrelated healthy control
subjects of European descent depicted as r2.
(Chang et al, 2016, Mol Neurobiology)
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3) LRP8 gene (from Li et al, Molecular Neurobiology, 2016


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4) Serotonin receptors (5-HT3) gene (HTR3A si HTR3B) (from Hammer et al, 2012)

5) PBRM1 gene (From Vassos et al, Biological Psychiatry, 2012)


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II. The morbid risk (MR) (recurrence risk) for bipolar disorder and other major
psychiatric disorders in first degree relatives of Romanian bipolar I patients

a) The morbid risk in first degree relatives by age of onset (AO) group of probands

It is known for decades from genetic epidemiology studies that the recurrence (morbid) risk of

major psychoses in patient relatives is not uniform across ages (Taylor and Abrams, 1981; Gershon

et al, 1982; Rice et al, 1987, Grigoroiu-Serbanescu et al, 2001). The disease AO is related to the

familial genetic burdun and to the parental transmitting side with earlier AO induced by the paternal

transmission (Grigoroiu-Serbanescu et al, 1997; 1998). Another factor that might influence the AO in

patients might be the father’s older age ( > 35) at offspring birth especially in sporadic cases

(Grigoroiu-Serbanescu et al, 2012).

Therefore we estimated the morbid risk (MR) for BP-I and for all major psychoses (BP-I, BP-

II, recurrent unipolar major depression, schizoaffective disorders, and schizophrenia) in relatives by

AO in proband patients.

The MR in first degree relatives was estimated separately for BP-I and combined for all major

psychoses (BP-I, BP-II, recurrent unipolar major depression, schizoaffective disorders, and

schizophrenia). The estimated risk figures are based on 2938 first degree relatives of 621 BP-I

patients. The relatives were investigated either through direct interview or through family history

method applied to the proband patients.

The overall MR for BP-I was 7 % (122/2938) and the MR for all affective psychoses,

schizoaffective psychoses and schizophrenia was 17% (337/2938 ) in the total sample of first degree

relatives (Grigoroiu-Serbanescu et al, 2014). The MR for BP-I in first degree relatives of BP-I

probands of 7% in the total Romanian sample is in line with previously published studies [Rice et al.

1987 (5.74% in American population of European ancestry); Maier et al., 1993 (7% in German

population); Lichtenstein et al., 2009 (6.4% in Swedish population)] and with our risk figure (5.3%)

previously found in a smaller subgroup of the current sample (Grigoroiu-Serbanescu et al., 2001).
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Since we were able to demonstrate through segregation analysis that AO of the bipolar I

disorder in probands is associated with different MR for major affective disorders to first degree

relatives (Grigoroiu-Serbanescu et al, 2001), we investigated the relationship between AO bands in

probands and the MR in relatives. The age of onset (AO) of BP-I in proband patients was subdivided

into two ways: a three AO-group and a two AO group based on commingling (admixture) analysis.

Thus, the three AO groups had the following limits: early onset = AO ≤ 21 years; intermediate onset

= AO between 22 and 34 years; late onset = AO > 34 years. The limits of the AO groups under the

two-AO-group model were: early onset = AO ≤ 24 years, late onset = AO > 24 years.

The MR are displayed in Table 3 and Table 4 extracted from our publication Grigoroiu-

Serbanescu et al, Journal of Affective Disorders, 2014, presented below.


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In the three-AO-group classification we observed a lack of difference in MR for both BP-I and

for all major psychoses between first degree relatives of early onset (EO) probands and first degree

relatives of intermediate-onset probands, while the MR differences between the relatives of early

onset probands and the relatives of late onset (LO) probands were highly significant (P = 0.0006).

This suggests that probands’ intermediate onset (AO=22-34) does not confer a specific MR to

relatives, distinct from the risk conferred by the EO in probands (AO ≤ 21).

Under the two-AO-group model the difference in MR between the relatives of EO probands

(AO ≤ 24) and the relatives of LO probands (AO > 24) was significant for both BP-I (P = 0.0006) and

for all major psychoses (P = 0.010).

We also observe that the MR for BP-I and for all major psychoses in relatives does not change in

the proband AO interval 22-24 years if we compare the MR figures in the onset group with AO ≤ 21

years with the onset group with AO ≤ 24 years. The MR to first degree relatives significantly

decreases only after age 34 for all major psychoses (χ2 = 3.85, P = 0.050 for the comparison between

the AO-band >29 years and AO-band >34 years). The MR for BP-I smoothly decreases across

successive proband AO bands.

b) The morbid risk by gender of first degree relatives and AO-group of probands

Under the three-AO-group classification the MR for both BP-I and all major psychoses in first

degree relatives did not differ by relative gender in any AO-group. Under the two-AO-group

classification the MR for BP-I was similar for male and female relatives of probands in the EO group,

as well as in the LO group. As regards the MR for all psychoses, this was similar for male and female

relatives of EO probands but significantly higher for female relatives (17%) than for male relatives

(11%) of LO probands due to a higher prevalence of unipolar major depression in women (χ2 = 6.46,

df = 1, P = 0.004).
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As a general conclusion based on MR to first degree relatives, we may state the MR for affective

disorders and schizophrenia remains constant up to proband AO 29 and visibly decreases after

AO 34.

III. Developmental psychopathology of offspring of BP-I patients

The primary purpose of developmental studies is the prevention of full blown disorders. But
unfortunately, currently this is not possible for any major psychosis. Thus, the developmental psych
opathology studies may serve derived purposes like the early risk detection, referral to mental health
services for treatment when available, and monitoring of the subclinical or clinical symptoms.
We summarize data from Rasic D et al. (Schizophrenia Bulletin, 2014) who conducted a meta-
analysis of 33 studies with relevant results selected among 3,962 family or offspring studies
published by 2012. The analysed sample consisted of 3863 offspring of parents with schizophrenia,
bipolar disorder and unipolar major depression. In this meta-analysis sample were included offspring
aged 10-17 of Romanian BP-I parents and Romanian controls, as well as offspring aged 10-17 of
Romanian parents with recurrent unipolar major depression and controls from the studies Grigoroiu-
Serbanescu M et al. Journal of Affective Disorders, 16, 1989, 167-179) and Grigoroiu-Serbanescu et
al., Rom. J. Neurology and Psychiatry,1, 1990, 45-62 (see Figure below). Rasic et al. show that the
relative risk for any psychopathology remains constant in offspring of parents with major psychoses
before and after age 20 being nearly three times higher than in offspring of normal parents.
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Relative risk for psychopathology before age 20 (comparison probands – controls)

Relative risk for psychopathology


psychopathology after age 20 (comparison probands – controls)
(From Rasic et al, Schizophrenia Bulletin, .2014, 40 (1) :28-38).
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Lifetime rates of major psychopathology in offspring of parents with BP disorder are presented
in the table below. These figures are compiled from different high risk studies.

Table. Lifetime psychopathology rates in offspring of parents with BP disorder

Disorder Offspring of BP parents

Schizophrenia 4%

Bipolar disorder 6%

Depression 14%

Anxiety disorders 27%

Disruptive behaviour 14 %

Substance use 15 %

ADHD 14 %

Any disorder 60 %

Structure of the psychopathology in adolescent offspring aged 10-17 of Romanian bipolar I


parents

The overall psychopathology rate in offspring aged 10-17 of bipolar parents was 61% using DSM-
III-R diagnostic criteria (APA, 1987) and the K-SADS-E interview (Puig-Antich et al., 1981)
compared to 17% in children of the general population in the same age range (6019 children)
randomly selected in a nationwide epidemiological study of 15,300 Romanian children. (Grigoroiu-
Serbanescu et al., Journal of Affective Disorders, 1989; Grigoroiu-Serbanescu et al, 1999).
The prevalent psychopathology that significantly differentiated offspring of bipolar parents
from offspring of normal parents and from offspring of the general population included: depressive
disorders (unipolar major depression, minor depression, dysthymic disorder), anxiety disorders
(overanxious disorder, phobic disorder, avoidant disorder, adjustment disorder with anxious mood,
18

simple phobias), ADHD and traits qualifying for future personality disorders (hyperthymic,
histrionic, avoidant, schizotypal).
The structure of the psychopathology varies by offspring sex in childhood and adolescence.
The depressive and anxiety disorders are more frequent in girls, while ADHD and conduct
disorders are more frequent in boys. In the age range 10-12 anxiety disorders prevail over disorders
of depressive spectrum. The frequency and severity of depressive disorders increases with age.
(Grigoroiu-Serbanescu et al., Journal of Affective Disorders, 1989).

Predictors of the severity of psychopathology in offspring of BP parents are: the severity of the
illness of the BP parent as measured by the total number of illness episodes, the psychopathological
status of the non-bipolar parent, the age of the BP parent at illness onset. The number of manic and
mixed episodes in the affected parent seems to have a higher contribution to the psychopathology
severity in offspring than the number of depressed episodes. (Grigoroiu-Serbanescu et al., Journal of
Affective Disorders, 1989).

Psychological disturbances.
Psychological disturbances are found at emotional regulation and cognitive functioning level.

Specific personality traits in offspring of BP I parents are:

Hyperthymic personality traits and hyperthymic personality disorder (Grigoroiu-Serbanescu


et al, Journal of Youth and Adolescence, 1991).
Depressive reactivity accompanied by anxiety, emotional instability, intolerance to
frustration (Grigoroiu-Serbanescu et al, 1991; 1993).

Molecular data available for genetic counseling in psychiatric disorders ?

NOT YET !
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Prevention: What can be prevented in offspring?

• Adjustement reactions with depressed or anxious mood;


• Drug addictive behaviour;
• Stressing undesirable personality traits.
• Dissocial behavior

What CANNOT be prevented in offspring ?

All major psychoses


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