4.2 G ENE VARIANTS OF 5-HTT IN ASSOCIATION TO MDD AND SCZ
4.2.6 Impaired decision making as a candidate endophenotype of BPD (Paper VI)
When we found the highly significant association between TPH-1 and a population of suicidal BPD women reported in Paper II, other members of our group failed to obtain similar results with a group of suicidal patients with mixed gender and diagnoses (De Franciscis et al., unpublished data). The results were somewhat unexpected, as the hypothesis of a biological association between BPD and the serotonin system was based mainly on suicidal behavior, common in BPD patients. It should be noted, however, that the BPD group had been selected for severe suicidality, and the subsequent suicide mortality in this group has been much higher than in our comparison group of suicide attempters. Thus, we cannot know whether the gene variant was primarily associated with BPD or with severe suicidality. The results led us to hypothesize that a disturbance in impulse control might associate with TPH-1. We therefore conducted a study, in collaboration with Arne Öhman’s group at Karolinska Institute to test for association between the specific TPH-1 gene variant previously found associated with BPD women and impulsiveness in decision-making.
Impulsiveness was measured using the Iowa Gambling Test (IGT), originally devised to score cognitive deficits following brain damage (see Paper VI). The TPH-1 gene variant ACGCCG (see previously shown Table 6c) was significantly more common
among low IGT performers (Figure 7b). We therefore propose that impaired decision-making is a potential endophenotype of borderline personality disorder.
Figure7a. Net scores (number of choices from good decks minus choices from bad decks. at the Iowa Gambling Task (IGT) showed a linear improvement over five blocks of 20 cards each (a total number of 100 cards), F(1,76)=49.58, P<0.001. This improvement was stronger for controls compared to BPD patients, F(1,76)=3.01, P<0.04 (one-tailed), and the groups differed significantly across the last three blocks, t(76)= 2.05, P<0.04 (two-tailed), but not the first two blocks, t(76)<1.
Figure7b. The TPH-1 haplotype was carried by 35% of the BPD patients with low IGT performance versus 12% of the BPD patients with higher net scores (χ2[1, N=42] =5.4, P<0.02).
5 COMMENTS & CONCLUSIONS
The objective of these studies was the identification of risk gene variants within a classical case-control study design. Approaches to construct haplotypes carrying risk for disease are generally complex, and when this study began information available on haplotype blocks was limited, and extensive genotyping and/or sequencing would have been required in all subjects within a study population, a prohibitive effort for most research groups. To make this project realistic, we introduced a hypothesis-based screening strategy that would reduce complexity. Using this approach, only a small number of samples were sequenced in limited regions, and the comparatively low number of markers found necessary to carry out haplotype analyses made cost and time acceptable even to small research groups. Overall, the study design allowed the reconstruction of informative haplotype markers using a simple strategy. Several significant associations were observed between the chosen serotonergic genes and different psychiatric disorders.
Analyses done with individual polymorphisms mostly yielded in weak associations at both allelic and genotypic levels. This was to be expected, as single-locus association studies are prone to generate weak associations, as well as inconsistent reproducibility across replica studies. Parent-offspring transmission of genetic variants follows certain constraints that could partly explain the poor reproducibility of the association studies outcome. Sample size is also factor to consider which may lead to false negative results, as common variants with small effects are difficult to detect.
The results obtained from 5-HTT association studies are worth some additional considerations. After a large number of genetic association studies done on this gene, the conclusions obtained from meta-analysis (see Introduction, section 1.8.1) diverge from the “popular consensus” notion that the gene is associated with depression. Also, association with SCZ, not widely acknowledged in the field, according to meta-analysis is reliable, although related to STin2 not to the more popular 5-HTTLPR (see Introduction, section 1.8.1). Interestingly, our data on 5-HTT are fully in agreement with meta-analysis conclusions, suggesting that the approach is both sensitive and specific.
In the course of gene-base haplotype association analyses, several haplotypes were identified that may carry risk for a disease, but also some with an opposite pattern, potentially “protective”. Such knowledge may contribute to future genetic assessments, such as gene functional studies, through which one might gain more insight into the possible role a gene may have in “normal” human physiology versus pathophysiology.
Differences were sometimes observed in LD values between groups, although mostly not significant. These may be related to population stratification. For instance, as noted in the Materials & Methods, our BPD patients also had one to several diagnoses on Axis I. Alternatively, as further discussed below, in certain cases there might be other reasons more pertinent to disease pathogenesis.
Although we tried to match our controls, a number of hidden phenotypes are likely to exist because of limited knowledge in biological psychiatry. Another major limitation in our studies was sample size, as well as lack of replica groups. Therefore, as noticeable in the abstracts of individual papers, it was carefully avoided to draw strong conclusions for associations with P-values just below the significance level, even though Bonferroni correction was used. This correction for multiple testing is very conservative, particularly in these studies, where measurements were not independent since most SNPs were in LD. This was done with the awareness that association studies are influenced by several factors, with phenotypic stratification probably being the most common in the case of complex psychiatric disorders. The results of this thesis work should therefore be interpreted with caution until replicated.
6 SUMMARY IN PERSIAN
7 ACKNOWLEDGEMENTS
I would like to state my gratitude and appreciation to everyone who has helped and supported me during my years in KI and through my work.
Particularly I would like to thank:
My adviser, Dr
Rosario Leopardi,
for providing me with a good combination of advice and independence, for sharing your experiences and ideas, and for believing in me;Professor
Marie Åsberg,
my co-adviser, for giving me the opportunity to initiate my research at KI and your support through these years;Rinat Gizatullin
, for teaching me the fundamentals of PCR and always making time to solve my “gel and band” problems; without you, the experimental work would have been difficult;Lisbeth Eriksson
, for being so kind and helpful, for all the small talks in your office and always being on top of the administrative work; Du är en riktig pärla!Erik Jönsson
, for your collaboration and constructive comments on my manuscripts, for always being nice and taking the time to answer my questions.Lars Terenius, Lotta Maurex, Arne Öhman, Alexander Wilczek, Åsa Nilssone,
andEwa Ahnemark
, for your collaborations and valuable contributions to my work.
Lotta Arborelius
, for introducing me to animal research;Salim Mottagui-Tabar
, for all your help regarding Arlequin;All the former and present fellow researchers at
CMM:
The groups of
Lars Terenius, Georgey Bakalkin, Tomas Ekström, Mats
Persson, Catharina Larsson, Björn Johansson,
andGunnar Nordstedt
, forproviding nice working environment and the friendly group of
Yasmin Hurd
for theinteresting journal clubs. Though, I would specially like to mention:
Agneta
, for all your help during my time in CMM but most of all thank you for being a dear friend; for listing, giving advice, for our bike tours and for trying to cultivate me more!Ming
, for being the best room-mate ever; I’ll always cherish our conversions about life; thank you for being a great listener and being my friend;Caterina
, Grazie per l'amore e l'affetto genuino. Grazie per il tuo incoraggiamento di ogni mattina, per tutti i pranzi a cui mi hai invitato e per tutti i regali e le riviste. Mi hai veramente viziato. I miei giorni al CMM non sarebbero stati gli stessi senza di te!Delphi & Tatjana
, for always being helpful and accommodating;Bodil, Jamileh, Nazli, Fayezeh, Mohsen, Anna Sillén, Jia Jing, Yin-choy, Anna Persson, Mark, Zoya, Niklas
, andDaniel U
(the IT- connection!): I’ll always carry a picture of your friendly smiles in my mind. Thank you for making the work atmosphere more amiable;Anestis,
although not always my ally, thanx for an enjoyable company, not to mention all your special treats;My “little” Dutch friend
Susanne
, you’ve surly brought joy and laughter into these past durable months of my life! Thank you for your friendship!☺I would also like to express my appreciation to all my dear friends in life outside of CMM, who have cared and supported me tremendously.
Specially,
Parisa,
Thank you for being such precious friend! For all the fun times during our sleepovers, dinners, our heavy “psycho-talks”, and of course all your peptalks…you have listened to my constant nagging and have cheered me up whenever I was down (but not always with an appreciative method!!)…Thank you for being a Pari!Daniela,
Thank you for being my genuine friend; thoughtful, comforting, kind and always with a great smile! Thank you for all your support and the fabulous memories through the years!Roshan
, Thank you for saying the first salam in San Diego! For all the lunches at KS, Persian concerts but mostly for being a true friend trough my rough times.Additional ThanX to:
Aniqa,
for our unique friendship but above all thanks for your support during this past year;Abtin
, for always being able to count on you, for the movie-nights at saloon Solna! Though especially for the laughs you bring along teasing me!Payman
, for all the fika’s in Kista and for (almost always) being on my side!Stina & Simret
thank you for being kind and caring, for all the lunches at MF andon the CMM balcony & thank you for being darling friends!
Naimeh & Puneh
, forbeing sympathetic friends although we are too far apart; I long for a Lillatorget visit!
Sara banoo
, for still being my no1 Darling!Shirin
a company full of action&
Giannis,
my private physician, thanx guys for all the fun hangouts and persuasions for diving;Shahriar
, ostad é azam! for all the interesting and deep discussions, you’re always cheerful!Shiva, Peiman, Elham, Kia
, andNavid,
for happy dinners &Levinsky-times;
Sara & Nina-Maria
, for our girly dinners, I miss you girls!Kristina
, my “oldest” friend, for always giving me hope and being supportive☺.Maman Nazi,
thank you for your endless love and your prayers!My angel sister
Maral
, thanx for your continuous encouragement and interest in my work, but most of all for being the best Zaboli sister ever!Maman & Baba
, who I am today, is simply because of you; Merci for sharing my experience!Shahram
, I’m grateful for each day that I’ve had you in my life….your endorsement through this period is beyond any words…I’m thankful for your love, patients, compassion & kindness…Ghazal Zaboli
Stockholm, 2006-05-10
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