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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.
2
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).
Table nr. 1. Genes conferring risk for bipolar disorder in the Romanian population
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
21
AL157359.4 rs78015114 Assoc = T P = 1.25E-8* Discovery/ Lithium response
(T/C) Hou et al, Lancet, 2016
21
17. AL157359.3 rs74795342 Assoc = G P = 3.00E-9* Discovery/ Lithium response
(G/A) Hou et al, Lancet, 2016
21
AL157359.3 rs75222709 Assoc = T P = 3.14E-9* Discovery/ Lithium response
(T/G) Hou et al, Lancet, 2016
21
5
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
8
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
2) CHDH gene first discovered in the Romanian sample (From Chang et al, Molecular
Neurobiology, 2016)
4) Serotonin receptors (5-HT3) gene (HTR3A si HTR3B) (from Hammer et al, 2012)
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
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
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).
13
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
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-
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
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
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).
15
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.
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.
16
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.
Schizophrenia 4%
Bipolar disorder 6%
Depression 14%
Disruptive behaviour 14 %
Substance use 15 %
ADHD 14 %
Any disorder 60 %
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.
NOT YET !
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