Exploration of experiences with and understanding of polygenic risk scores for bipolar disorder

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Exploration of experiences with and understanding of polygenic risk scores for bipolar disorder Sophie Putt , Tatiane Yanes , Bettina Meiser , Rajneesh Kaur , Janice M. Fullerton , Kristine Barlow-Stewart , Peter R. Schofield , Claudio Toma , Holly Peay , Philip B. Mitchell PII: DOI: Reference:

S0165-0327(19)31581-2 https://doi.org/10.1016/j.jad.2020.01.037 JAD 11486

To appear in:

Journal of Affective Disorders

Received date: Revised date: Accepted date:

16 June 2019 27 November 2019 11 January 2020

Please cite this article as: Sophie Putt , Tatiane Yanes , Bettina Meiser , Rajneesh Kaur , Janice M. Fullerton , Kristine Barlow-Stewart , Peter R. Schofield , Claudio Toma , Holly Peay , Philip B. Mitchell , Exploration of experiences with and understanding of polygenic risk scores for bipolar disorder, Journal of Affective Disorders (2020), doi: https://doi.org/10.1016/j.jad.2020.01.037

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier B.V.

Highlights 

Complex polygenic information regarding BD is well understood by recipients



People living with BD may benefit from polygenic testing to alleviate guilt and blame



Receiving an unexpected test result may cause transient shock and/or distress

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Individuals may choose not to receive results given their stage of life or recovery

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Future providers of polygenic testing for BD may now better understand its impact

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Exploration of experiences with and understanding of polygenic risk scores for bipolar disorder

Sophie Putt a, Tatiane Yanesb, Bettina Meiserb, Rajneesh Kaurb, Janice M. Fullertonc,d, Kristine Barlow-Stewarte, Peter R. Schofieldc,d, Claudio Tomac,d, Holly Peayf, Philip B. Mitchellg,h a

University of New South Wales Medicine, Sydney, NSW 2052, Australia

b

Prince of Wales Clinical School, University of New South Wales, Sydney, NSW 2052, Australia

c

Neuroscience Research Australia, Randwick, Sydney, NSW 2031, Australia

d

School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia

e

Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW

2000, Australia. f

National Human Genome Research Institute, Bethesda, United States

g

School of Psychiatry, University of New South Wales, Sydney, NSW 2052, Australia

h

Black Dog Institute, Prince of Wales Hospital, Sydney, NSW 2052, Australia

Corresponding author: Sophie Putt Psychosocial Research Group, Prince of Wales Clinical School Level 4, Lowy Cancer Research Centre C25 The University of New South Wales (UNSW) Sydney NSW 2052, Australia Email: [email protected] Telephone: 61 2 9385 0025

Declarations of interest: Bettina Meiser has a remunerated consultant role with the company AstraZeneca with respect to an unrelated project. The other authors have no conflicts of interest. 2

Abstract Background: Polygenic risk scores (PRSs) summarise genetic risk in complex genetic disorders such as bipolar disorder (BD). The aim of this study was to gain in-depth, nuanced information regarding the understanding and experience of receiving a PRS for BD from individuals who already have a BD diagnosis. Methods: Participants from a previous genetics study were invited to receive their PRS in a face-toface consultation with a genetic counsellor or psychiatrist. Four weeks later, semi-structured interviews were conducted, with 14 ‘acceptors’ (those who chose to receive their PRS) and 4 ‘decliners’ (those who did not wish to receive their PRS). Results: Four themes were developed: (1) An easy decision, (2) A positive experience, (3) The grey area, and (4) The future is exciting and frightening. Despite some reported initial shock and distress, all acceptors described the experience of receiving their PRS as a positive one. It allowed them to better understand their condition and/or reduced feelings of self-blame. Decliners chose not to receive their results because of a lack of perceived usefulness or concern that PRS may hinder personal recovery. Limitations: Given the qualitative design of the study, statistically valid generalisations cannot be undertaken, nor can causal relationships be established. Conclusions: PRS for BD were generally well accepted and understood. Knowledge regarding the impact of PRS for BD ensures that counselling frameworks are responsive to patient needs as well as informing education for psychiatrists and genetic counsellors, who will play pivotal roles in future polygenic testing provision.

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Key Words: Bipolar disorder; polygenic risk score; genetic testing; attitudes; experiences; understanding1

Introduction Bipolar disorder (BD) is a chronic, recurrent mood disturbance that affects 1-1.5% of the global population (Merikangas et al., 2011). BD is characterised by pathological mood episodes of mania (BD-I) or hypomania (BD-II) and depression, resulting in changes to energy levels and behaviour (Anderson et al., 2012). BD represents a major health burden often leading to cognitive, social and functional impairment and carries a 15-20% lifetime risk of suicide (Schaffer et al., 2015). Twin studies demonstrate a strong heritable contribution to BD, with genetic factors estimated to account for approximately 85% of the risk for the condition (Bienvenu et al., 2011; Rasic et al., 2014). Individuals with a first-degree relative with BD have approximately a ten-fold increased risk of developing the condition when compared to the general population (Smoller & Finn, 2003). Unlike conditions with single-gene Mendelian inheritance, BD involves a polygenic contribution to risk. This means there are many contributing genetic variants (single nucleotide polymorphisms, SNPs) of individually small effect that contribute to the risk of developing BD (Craddock & Sklar, 2013; Psychiatric GWAS Consortium Bipolar Disorder Working Group, 2011).

To date, genome-wide association studies (GWAS) have identified SNPs that are significantly associated with BD at 30 independent loci (Stahl et al., 2019). Individually, each of the diseaseassociated variants contributes minimally to BD risk (<1%); however, it is estimated that variation across many thousands of SNPs together contributes a substantial proportion (i.e. 25-40%) of the percentage of phenotypic variance at a population level (Lee et al., 2011; 2013). 1

Abbreviations: bipolar disorder (BD), genome-wide association study (GWAS), polygenic risk

score (PRS), single nucleotide polymorphism (SNP).

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The combined effect of the common variants identified via GWAS can be expressed as a polygenic risk score (PRS) (Mistry et al., 2018). The PRS is determined by summing the risk associated with each SNP carried by an individual with weighting by the effect size of each variant, expressed as the per-allele odds ratio (Wray et al., 2014). The PRS method shows significant increases in the mean genomic load of risk variants in people with BD compared to unrelated controls (Fullerton et al., 2015). It also shows statistically significant mean increases in groups of at-risk youth compared to unrelated controls, as well as people with BD compared to people with schizophrenia (Fullerton et al., 2015; Robert et al., 2015; Ruderfer et al., 2013).

PRSs are not yet of sufficient specificity or precision to categorize people in terms of their diagnostic status on an individual basis (Palk et al., 2019). In the most recent GWAS, SNP heritability only explained ~8% of the phenotypic variance in BD (Stahl et al., 2019). However, the performance of PRSs is expected to improve further with increasing sample sizes and subsequent identification of additional common and rare genetic variants (Wray et al., 2014). Additionally, PRSs delivered via a well-developed genetic counselling protocol may provide individuals and families with potentially valuable probabilistic information. In the future, polygenic testing may help to ensure early, accurate diagnosis of BD when used as an adjunct to clinical assessment (Fullerton et al., 2015; Mistry et al., 2018).

Before polygenic testing enters clinical practice, it is crucial to assess future consumers’ attitudes, interests and expectations, as well as the perceived benefits and concerns of testing. No study to date has returned PRSs for BD to individuals and as such, all current knowledge is based upon hypothetical scenarios. Five major studies reveal a high level of interest in hypothetical genetic testing for BD (Jones et al., 2002; Meiser et al., 2008; Meiser et al., 2005; Smith et al., 1996; Trippitelli et al., 1998). Interest, whilst universally high, is seen to correlate with the degree of 5

certainty with which any test would signify the development of BD. Interestingly, reported intention to undergo psychiatric genetic testing remains high regardless of whether or not treatment or prevention exists (Laegsgaard et al., 2009). Hypothetical interest in genetic testing for BD is not expected to translate directly into actual test uptake, as has been found for familial cancer (Lerman et al., 2002) and Huntington’s disease. Of people at risk for Huntington’s disease, 40-79% indicate interest in testing; however, only 9-20% actually undergo testing (Meiser & Dunn, 2000).

The aim of this study was to gain in-depth, nuanced information regarding the experiences and understanding of PRSs amongst affected individuals at different levels of polygenic risk for BD. The study, which focused on people with established BD, also examined individuals’ decisions to receive or decline a PRS. This translational research may provide the foundation for the optimal and responsible utilisation of polygenic testing for BD in the future.

Methods Sampling and Participants This study was approved by the Human Research Ethics Committee at UNSW (HC180051). Purposive sampling strategy was employed (Patton, 2002), with participants selected for inclusion if they had a formal diagnosis of BD, had already provided a blood sample which had undergone genome-wide genotyping as part of the Bipolar Disorder Clinical and Genetic Study at the Black Dog Institute (HC15299), were of Caucasian ancestry (based on genetic principal components analysis), were fluent English speakers and aged ≥18 years. To obtain a range of perspectives on genetic testing, participants were invited to participate regardless of their decision to receive their results.

Eligible participants were sent a study invitation package that included a notification of the availability of genetic testing results, the study information and consent forms, a pamphlet on 6

polygenic testing and BD (Supplementary File 1), and response sheet/opt-out form. Participants who did not return the study consent form or opt-out form were followed up via telephone three weeks post-mail-out by SP. Participants who provided informed consent and indicated on the response sheet that they would like to receive their personalised PRS were contacted by SP by telephone to arrange a consultation time for them to receive their results.

Polygenic Risk Score Calculation PRSs were calculated as described by Wilcox et al. (2017) using summary statistics from the primary BD GWAS conducted by the Psychiatric Genomics Consortium (Psychiatric GWAS Consortium Bipolar Disorder Working Group, 2011). A p-value threshold of PT<0.2 was used, which included 66,764 independent SNPs across the genome. The distribution of PRS in a population of individuals with established BD (n=234 cases) was compared to control individuals (n=248). Participants were broadly grouped into low PRS (bottom quartile), high PRS (top quartile) or intermediate PRS (middle two quartiles).

Genetic Counselling Participants who chose to learn their PRS (‘acceptors’) attended a face-to-face consultation with a genetic counsellor (TY) or a psychiatrist (PM) with expertise in the field of psychiatric clinical genetics. These consultations took place at the Black Dog Institute and the University of New South Wales, Sydney and ranged from 40-110 minutes. The development of a model of genetic counselling for the delivery of PRS was informed by the literature (Peay & Austin, 2011) and refined in an ongoing manner by the clinical expertise of investigators KBS, TY and HP.

Genetic counselling sessions began with an exploration of participant’s personal and family experiences with BD and understating of disease causality and risk (Supplementary File 2). Participants were then given information about the causes of BD. The ‘mental illness jar model’ 7

described by Peay and Austin (2011) was used to assist understanding of the roles of genetic and environmental risk factors in BD. Participants received their personal PRS and population percentile score plotted on a bell curve relative to the BD population and the general population (Supplementary File 2). Participants were informed about the possibility of additional genetic factors yet to be discovered contributing to their condition. The personalized nature of PRS was also discussed, including that this information cannot be used to estimate risk to family members.

Finally, participants were given take-home copies of their PRS graph, a textual explanation of the graph and handouts on BD management.

Data Collection Semi-structured, in-depth telephone interviews were conducted up to four weeks after acceptors had received their PRS and were continued until data saturation was achieved; that is when few new data were being gathered (Bryman, 2012). All interviews were conducted by SP from July-October 2018. Interviews were conducted via telephone in order to increase convenience for participants and to allow greater perceived anonymity so that participants could freely discuss sensitive topics. The interview guide focused on eliciting information about causal attributions for BD, attitudes toward genetic testing for BD, the experience of receiving a PRS and participants’ understanding of polygenic testing (Supplementary File 3). Interviews lasted an average of 52 minutes (range: 31-96 minutes), were digitally recorded and transcribed verbatim. Transcripts were deidentified and participants were assigned pseudonyms. To further preserve anonymity, participants’ ages have been omitted from the quotes in the results section.

Data Analysis The data were subjected to a rigorous qualitative analysis guided by the thematic analysis framework described by Braun and Clarke (2006). Transcripts were analysed iteratively from an 8

essentialist/realist perspective, which assumes that meaning and experience is articulated through language (Potter & Wetherell, 1987). A hybrid approach of inductive and ‘theoretical’ coding and theme development was adopted (Braun & Clarke, 2006). The qualitative computer program NVivo 12 (QRS International) was used to assist in the organizational aspect of coding.

Rigor and Reflexivity To ensure rigor, the research team engaged in a constant reflexive process (Angen, 2000). From the onset of the study a reflective journal was kept by SP, who conducted recruitment, data collection and analysis. This journal served as an audit trail, documenting all methodological decisions, and fostered critical self-awareness by documenting any assumptions and preconceptions held by SP as a young, female medical student. SP noted that her medical training allowed her to understand participants’ perspectives and also made her aware of the complexity of genetic testing and the way in which medical tests are often oversimplified and overvalued by patients. SP also noted that during preliminary research she was surprised by the strong interest in psychiatric genetic testing and largely positive attitudes held by individuals and families. This may have influenced her reaction to participants’ responses and therefore 20% of transcripts were coded by two independent researchers (BM, a psychosocial researcher, and TY, a genetic counsellor) to foster reflexive dialogue. Rigor was further enhanced by paying special attention to negative cases (Mays & Pope, 2000).

Results Out of the 92 eligible participants invited to this study, 12 declined to participate, one had passed away and 15 letters were returned to sender. Twenty-three individuals consented to participate in the study, yielding a participation rate of 25%. Mean age of participants was 51 (range 29 and 73 years). Of the 25 participants, 14 opted to receive their personalized PRS (‘acceptors’) and four chose not to receive their score (‘decliners’) (Table 1). The remaining five individuals who had 9

initially consented to participate either failed to attend their consultations or opted to withdraw from the study as they were clinically unwell. Approximately half of the acceptors had a first- or seconddegree family member with BD and/or major depressive disorder (MDD) (57%), whereas only one decliner had a positive family history (25%). A majority of acceptors (71%) and a minority of decliners (25%) had children. [Insert Table 1 about here]

Theme 1: An easy decision Decision-making Exemplary quotations regarding the decision to receive results can be found in Table 2. Most acceptors described the decision to receive their PRS as an easy one that did not require too much thought. One participant “jumped” at the opportunity to receive her result, despite having to travel interstate for the consultation. For her it was also a simple decision that wasn’t too deeply thought out.

Most decliners felt strongly about their various reasons for choosing not the receive their PRS, and thus, similarly to the acceptors, the decision was also described as a simple one. A few decliners believed that polygenic testing was not useful for older individuals, or for people who do not have children. One participant chose not to receive her result as she did not believe there was currently enough evidence to propose a genetic model for BD. Although this decliner recognized the familial aggregation of BD, she did not believe that genes played a significant role in its heritability.

A few participants believed that receiving a PRS for BD would negatively impact their journey to recovery. After being diagnosed, these participants found themselves identifying strongly with BD at the detriment of their health and wellbeing. For these participants, establishing an identity outside of BD has been instrumental in the recovery process. It was very important for these individuals to reclaim aspects of their personality such as their creativity or “quirkiness”, which were previously 10

seen as symptoms of their condition. These participants believed that receiving a PRS may result in further identification with BD, which would disturb their recovery journey.

Valuing Knowledge and Truth Most acceptors placed great significance on the power of information. They were motivated to receive their PRS as they believed in the importance of discovering the truth about themselves, irrespective of the result. These participants spoke about how “knowledge is power” and that information should be discovered and not feared. A substantial proportion of acceptors were motivated by curiosity and the idea of discovering why they may have developed BD. This view was expressed by acceptors exclusively.

Some acceptors acknowledged that finding an explanation for their condition would be “nice” but would not alter their current situation. Amongst the participants who already suspected a genetic link to their BD, a common reason for receiving their PRS was to confirm and quantify this genetic link. [Insert Table 2 about here]

Theme 2: A positive experience Responses to receiving a PRS varied among acceptors and were largely influenced by whether the PRS aligned with the participant’s hopes and expectations, which in turn were informed by their lived experience of BD. All acceptors reported the experience as a positive one, and quotations illustrating their responses can be found in Table 3.

Confirming or challenging pre-existing beliefs Some acceptors had previously suspected a genetic contribution to their BD given a positive family history. For these participants, receiving a PRS did not have a significant emotional impact. It did, however, add a layer of proof and confirmation to previous beliefs about the role of genetics in their 11

condition. On the other hand, a significant proportion of acceptors received an unexpected result as they had not previously considered the role of genetics in BD, or they received a PRS that was higher than anticipated. These participants reported strong initial emotional responses, including feeling shocked, worried, vulnerable and overwhelmed. However, given time to process their PRS, participants’ initial feelings subsided, and they reported positive responses to their results.

Most of the participants who unexpectedly received results indicating higher risk felt relieved at the time of the interview as the PRS legitimized their condition and removed feelings of blame and guilt. One participant received an unexpectedly low result. Whilst she similarly reported initial feelings of shock and surprise, there was no evidence of the strong emotional reaction expressed by those who received unexpectedly high results. Despite this surprise, the participant reported an overall positive experience.

Most participants expected and were comfortable with the uncertainty that remains regarding BD genetics.

Removing self-doubt and denial Most participants reported hoping for a high or intermediate PRS as they believed it would confirm their diagnosis and remove any self-doubt.

Contrastingly, one participant was hoping for a low PRS as they were in a state of denial regarding their BD diagnosis. For this participant, receiving an intermediate PRS was a “sad” confirmation, however it helped her to accept her diagnosis.

Sharing the experience

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Most participants discussed the importance of having their PRS returned in a face-to-face setting by a health professional. This allowed a space for reflection, support and counselling.

All acceptors chose to share their result with at least one family member, friend or partner. The participants were eager to explain to the people who had witnessed their BD episodes that there was a legitimate reason for their behaviour; they were not “choosing to be difficult” and they may not necessarily be responsible for their actions.

Reinforcing management strategies All the participants were satisfied that they had adequate management strategies in place at the time of the interview and no one reported altering their management strategies or behaviours in light of their PRS. However, a majority of participants mentioned that receiving a PRS made them more conscious of the importance of adhering to their pre-existing management regimen. Interestingly, this was seen in participants who received a low PRS as well as high and intermediate results.

[Insert Table 3 about here]

Theme 3: The grey area Quotations pertaining to this theme can be found in Table 4.

A lot remains unknown Participants’ understanding was consistent with the information provided to them during the returnof-results consultation. Most acceptors seemed to understand the ‘gist’ of polygenic testing for BD. They were aware of the polygenicity of BD and that currently unknown genetic and environmental factors, or the “grey area” as described by one acceptor, means that the PRS provides a risk result only. 13

A few acceptors reported confusion regarding the graphical representation of their PRS. Some participants also reported the need to re-read the handouts to understand the information from the consultation.

Understanding inheritance Acceptors had a generally good understanding that alleles from SNPs may be randomly inherited from each parent, and that an affected individual may have received some genetic changes from their mother and/or father, even if that parent was unaffected. One of the acceptors who received a low PRS but has three children with BD was able to interpret a result that was discordant with her family history using this model of inheritance. She acknowledged that the PRS does not capture all risk factors and cannot be used to directly infer children’s risk.

Relative recall Most participants used relative terms to recall their PRS. Results were often described as higher or lower than the BD and/or general population average.

[Insert Table 4 about here]

Theme 4: The future is exciting and frightening Most participants were excited by, and optimistic towards the prospect of genetic testing for BD in the future, discussing various potential benefits. There was also a sense of fear as almost all participants reported at least one potential risk of future PRS for BD.

The future will be better for those with BD

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Each of the perceived benefits quoted in Table 5 reveals participants’ optimism towards future genetic testing for BD. These quotes reveal how the participants’ own lived experience has informed their attitudes, and their hopes that in the future, people with BD will not have to encounter what they had to.

The most frequently cited benefit of genetic testing for BD was the possibility for early and accurate diagnosis, and treatment with appropriate mediation. This can be understood in the context of the participants’ personal experiences, as most participants reported experiencing BD symptoms for 510 years before receiving a correct diagnosis. This period was often described as “hell” as they did not understand what they were experiencing and were often misdiagnosed and mismanaged. [Insert Table 5 about here]

Who knows what might happen? Both acceptors and decliners held fears regarding future genetic testing for BD and how it may affect individual’s mental state and privacy, as well as public perception.

Most of the perceived risks and fears arose from the participants’ understanding about the limitations and implications of genetic testing as evidenced by the quotes in Table 6. For example, all participants were aware that clinical and research genetic test results must be disclosed to life insurance companies in Australia. Whilst this did not impact the current cohort as they already had a diagnosis of BD, almost everyone cited insurance discrimination as a risk of genetic testing for BD in the future.

A few participants were concerned that genetic testing for BD may result in a sense of genetic determinism, and one participant was concerned that it may worsen the stigma associated with the condition. 15

[Insert Table 6 about here]

Discussion Most acceptors and decliners reported making prompt and instinctive decisions to receive or not receive their PRS, with many suggesting that it was not a hard decision at all. This non-deliberative manner of decision-making can be explained using the Fuzzy Trace Theory (Reyna, 2008). This theory is based on the dual-processing model of cognition, whereby individuals have two distinct mental representations of information, gist traces and verbatim traces. Gist traces (or ‘gist representations’) capture a subjective understanding of information based on experience, emotion, education, culture and worldview (Peters et al., 2006). Contrastingly verbatim traces are objective, literal representations of information (Reyna, 2008). Reliance on gist representations for decisionmaking increases with experience and time (Reyna, 2008). Therefore, one could assume that participants in this study had developed a significant propensity to use gist representations when making BD-related decisions as they were on average middle-aged and had experienced BD for many years. This may explain their quick, intuitive decision to receive or decline a PRS. Participants were universally pleased with their decision to receive a PRS and described the experience as a positive one despite some participants experiencing shock immediately post-results. This positive response can also be explained by the Fuzzy Trace Theory, which suggests that gistbased decision-making is associated with low levels of distress and decision regret (Biesecker et al., 2017; Pierce & Hicks, 2001).

Motivations for receiving genetic test results aligned closely with motivations documented in the literature (Facio et al., 2011; Gollust et al., 2011). That is, most people chose to receive their results to learn more about themselves and their health. According to the literature, the major reasons for choosing not to receive genetic test results include study logistics, privacy and discrimination concerns and worries regarding uncertainty (Amendola et al., 2018). Contrastingly, the current 16

study found that participants who chose not to receive their PRS were motivated by beliefs that: the process might hinder recovery, there was no perceived value in testing given older age and childfree status, and/or there was not enough evidence to suggest a genetic model for BD. Interestingly, this was the case despite participants having partaken in a previous BD genetic study. These novel findings are likely due to the nature of the study as it is the first to explore attitudes of decliners in the setting of psychiatric polygenic testing, whereas most of the literature examines predictive testing and focuses on physical conditions.

The participants who chose to receive their results used relative terms such as “higher than average” or “lower than average” to describe their PRS rather than recalling an exact numerical score. Similar findings were discussed in other qualitative studies that returned SNP information to individuals for prostate and colon cancer (Bancroft et al., 2014; Nusbaum et al., 2013). This can also be explained by the Fuzzy Trace Theory; if risk information (the PRS) is provided in graphical form, people tend to ignore verbatim numbers in favour of the salient gist relation, i.e. whether the score is higher or lower than average. Recalling gist representations suggests that the participant has not simply asked themselves ‘what is the score?’, but also considered ‘what does the score mean to me?’ (Reyna, 2008).

As well as having a good understanding of their own score, acceptors displayed a good understanding of the implications and limitations of polygenic testing for BD. High levels of understanding of polygenic testing have also been reported in the prostate cancer and breast cancer setting (Bancroft et al., 2014; Bancroft et al., 2015; Young et al., 2018). Acceptors could appreciate that polygenic testing for BD was in its infancy and that the PRS did not account for currently unknown genetic factors. Most participants spoke about how a person can be genetically ‘at-risk’ for BD but may not develop the condition. The participants’ high level of understanding is likely due to the way in which the PRS was contextualized for them during the comprehensive genetic 17

counselling session. It is important that future result provision occurs within a well-developed genetic counselling framework to ensure good understanding as there are major concerns that a high score may be misinterpreted as a diagnosis of BD or as a suggestion that the individual will definitely develop the condition. Such a misunderstanding may result in high levels of distress in the individual and/or their family (Peay & Austin, 2011).

Acceptors also displayed a sound awareness of the personalised nature of SNP inheritance. This may be because polygenic inheritance aligns nicely with lay notions of inheritance, which are founded in the concept of bilateral kinship, i.e. that offspring receive exactly half of their genetic material from each parent (Richards, 2016; Young et al., 2018). Decliners did not display similarly high levels of understanding. A few decliners mistakenly spoke of PRS as a diagnostic test, oversimplified the inheritance pattern of BD-associated genes or believed that genes were not an important factor in BD. This reiterates the notion that the genetic counselling accompanying result provision played an important role in assisting understanding.

Some acceptors received results that were either discordant with their family history or incongruent with their previous causal attributions for BD. These participants reported feeling initially surprised, distressed, shocked and/or vulnerable. Despite this, participants reported feelings of acceptance and relief after having had time to process their results. Participants who received an intermediate or high PRS were pleased to have an explanation for their condition and felt a reduced sense of guilt and responsibility for their BD. Those who received a low PRS also reported positive experiences, as they had come to a better understanding of their condition, and importantly, they did not report feeling increased responsibility for their BD. In the future, PRSs must be returned with careful consideration of individuals’ pre-existing expectations, as these may have the greatest impact on their emotional response.

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In accordance with past studies in prostate and skin cancer, no participants in the current study reported altering their behaviour since receiving a PRS (Bancroft et al., 2014; Smit et al., 2016). This is likely because the genetic counselling sessions did not encourage behaviour modifications based on the research PRS, and also because participants already had effective management strategies in place. However, most participants reported that receiving a PRS reinforced the importance of strictly adhering to their current management regimens. Interestingly, this finding was independent of the PRS received, which suggests that it may be a result of the education imparted by the genetic counsellor and/or psychiatrist.

Participants’ attitudes toward future genetic testing for BD largely aligned with findings from previous hypothetical studies. The outcomes relating to reproductive choices were mentioned by decliners only, which suggests that acceptors better understood how SNP information cannot be directly used to infer children’s risk. The perceived risks of future genetic testing for BD cited by participants also align closely with the literature, with a major focus on insurance discrimination and potential for distress (Meiser et al., 2005).

Most participants believed that a genetic explanation for BD would reduce the associated stigma. We also found that most participants who unexpectedly received results indicating higher risk felt that the PRS legitimized their condition and removed feelings of blame and guilt. By contrast, one participant was concerned that a genetic model for BD would increase the associated stigma. These contrasting findings highlight the need to elicit individuals’ views on the relationship between genetic explanations and stigma when providing genetic counselling to people with BD.

These seemingly contradictory findings reflect the multifaceted nature of stigma, which comprises emotional responses of blame, guilt, pity and fear. According to Weiner’s Attribution Model (1985), emotional responses to having a genetic explanation depend on causal attributions made by 19

individuals (Link et al., 2004). Guilt is likely to be alleviated when for example a parent of someone with BD perceives the cause as being brought about through genetics (an uncontrollable condition), rather than bad parenting (Phelan et al., 2002; Weiner et al., 1982). Attributing mental illnesses to genetics would also be expected to reduce blame, including self-blame (Phelan, 2002; Phelan et al., 200). By contrast, ‘genetic essentialism’ theory postulates that a genetic explanation for BD may exacerbate the seriousness of the condition and/or increase perceptions of the ill person as ‘defective’ or ‘different’, which in turn may give rise to fatalism, fear and/or pity (Phelan et al., 2002). Adopting an intermediate position between attribution theory and genetic essentialism, Phelan (2005) argues that these theories may not be mutually exclusive but may operate simultaneously. Consistent with this view are equivocal findings in previous studies on the contribution of a genetic explanation of BD, with both positive and negative effects of attributing the cause of one’s BD to genetic factors (Meiser et al., 2005; 2007).

The limitations of this study should be noted. Participants in this study had above-average education levels, which limits the ability of findings to be transferred to less-well educated populations. Recent research by Semaka and Austin (2019) found that psychiatric genetic counselling without PRS assisted individuals’ understanding regarding aetiology of their mental illness and allowed them to more fully integrate their illness into their sense of self. Thus, in the current study, uncertainty surrounds the extent to which observed responses were in relation to the PRS result itself versus the genetic counselling session. Also, participation in a previous genetic study may have altered attitudes and beliefs. The low response rate (25%) means that a variety of views may have been missed. It is highly likely that a significant proportion of eligible participants may have been experiencing serious mental distress at the time of study invitation and thus failed to respond. Additionally, the sample lacked cultural diversity as all participants were from the Anglo-Celtic majority culture, although this restriction was necessary to enable correct interpretation of the PRS results due to ethnic differences in allele frequency which might artificially inflate or deflate an 20

individual’s score. Finally, given the qualitative nature of the study, causal relationships cannot be established, nor can statistically valid generalisations be made.

Conclusion Given the rapid advances in psychiatric genetic research, it is likely that polygenic testing for BD will enter clinical practice in the not-too-distant future. Polygenic testing has the potential to provide individuals with valuable probabilistic information regarding their BD risk, and may be used by health professionals as an adjunct to clinical assessment for earlier, more accurate diagnoses. As demonstrated in the current study, polygenic testing may also be deeply meaningful for BD patients in reducing self-blame and stigma and reinforcing the need for strict adherence to management regimens.

This study found that complex polygenic information is highly acceptable and well understood by individuals with a BD diagnosis (at least when delivered in the context of a genetic counselling interaction), and that an individual’s lived experience with BD has a significant influence on their decisions, attitudes and responses. All post-test shock and/or distress was transient, with participants describing an overall positive experience and no decision regret at one-month postconsultation.

The study suggests that genetic counselling should accompany return of results, as participants valued the supportive, face-to-face consultation setting whereby they could talk about their experiences and have their questions answered. Indeed, the understanding and positive reaction to PRSs observed in this study may be because of the manner in which this information was provided that is, within the context of comprehensive psychiatric genetic counselling.

This study is the first step in a body of research that may inform the optimal and responsible utilisation polygenic testing for BD, and likely other polygenic mental illnesses, in the future. This 21

study explored the range of beliefs that individuals hold, and future work should assess the extent to which these beliefs are endorsed using quantitative designs. Future research could also explore the psychological and behavioural impact of polygenic testing in at-risk individuals who are currently unaffected but have a significant positive family history of BD. Such research requires prudence and caution as this information has greater potential for distress in asymptomatic individuals.

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Tables Table 1: Summary characteristics of participants (n= 18) Participant description

Acceptors (n=14)

Decliners (n=4)

n (%)

n (%)

52 (29-73)

48 (32-61)

High

6 (43)

-

Intermediate

5 (36)

-

Low

3 (21)

-

Females

8 (57)

3 (75)

8 (57)

1 (25)

Attended university

10 (71)

4 (100)

At least one child

10 (71)

1 (25)

Metropolitan

11 (79)

3 (75)

Non-metropolitan

3 (21)

1 (25)

Mean age (range) PRS

At least one first- or seconddegree relative with BD or MDD

Residence

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Table 2: Participants’ decisions to receive or decline PRS results Concept

Quotation/s

An easy

Decision-making

decision

I didn’t sort of wonder long and hard about [receiving my PRS]. I just sort of decided to go ahead with it because it was available. (Charles, High PRS) Pretty much all information I can get is potentially helpful. It wasn’t necessarily any more thought out than that. (Daisy, High PRS) Lack of usefulness Because of my age and I don’t have kids, I didn’t really see the value [of receiving a PRS]. (Claire, Decliner) Lack of evidence for a genetic model for BD The evidence for this genetic theory [is] so weak it’s not funny… Studies aren’t actually able to distinguish between the impact of I guess inheriting genes and the environmental factors. (Cate, Decliner) PRS may impede establishment of identity outside of BD I’m still in the process of now trying not to identify with [BD] so much and kind of be myself as I guess, the whole picture rather than just the bipolar diagnosis… that’s been so powerful for me and kind of yes empowering and positive. (Sue, Decliner) My energy and my creativity and my bubbly personality, they’re part of me, they’re not an illness, that’s who I am and I‘ve reclaimed those as me. (Cate, Decliner)

Valuing

Knowledge is power

knowledge

It’s much better to know than not to know. I can’t see the point of not knowing

and truth

stuff. (Mia, Low PRS) You shouldn’t be scared of the truth you should actually embrace it because it will give you something one way or something the other way. (James, Intermediate PRS) Curiosity I was actually very curious about exactly where [my BD has] come from because I didn’t really understand that. (Alice, High PRS) I have this problem in my life and it’d be nice to know that there’s a reason why in 24

a way, not that you need to know, not that it really changes anything but it’d be still nice to know. (Lucas, High PRS) To confirm a genetic link I always thought it was genetic with my grandma, and yeah – so [it was] just interesting to see how much of a factor that is. (Laura, High PRS)

Table 3: Participants’ responses to PRS results. Concept

Quotation

Confirming

No significant emotional impact amongst those with a strong family history

or

I wasn’t really hanging on the result, like it was interesting, but it’s not – not life

challenging

changing or anything…. it confirms the genetic link. (Laura, High PRS)

pre-existing

It was just like validation I guess. It’s interesting because I mean looking at my

beliefs

dad’s side it really does seem like it’s a genetic thing. (Phoebe, Intermediate PRS) Initial emotional responses amongst those who received unexpected results I didn’t actually ever think there was a genetic component. It’s not something that’s ever occurred to me... I was actually shocked when I got the score. I came home and cried and don’t ask me why I cried because I’ve got no idea. I just came home and the whole thing had just overwhelmed me but not necessarily in a bad way. I mean I reacted emotionally. (Alice, High PRS) I think I was initially a little bit shocked and I guess I’ve sort of lived with it for the weeks since… processed a little bit. I think it kind of, yeah… it helped me to have an explanation for [my BD]… that did help. (Charles, High PRS) PRS legitimized condition and removed feelings of blame and guilt I thought I was responsible for it, I didn’t know that there was a genetic link. It showed me that [BD] wasn’t something I elected, it was something that I’m probably predisposed to genetically... And that’s good, that takes a lot of the guilt that has been associated with my condition, it removes a lot of that. (Matthew, Intermediate PRS) I’ve suddenly realized that there are other elements at play that predisposed me towards getting this, that it’s not something that I’ve been engineering all by myself. Yeah, so it’s been enormously helpful. (Alice, High PRS) 25

Response to low PRS I was quite surprised because I was thinking, “Oh that’s low… how can it be that low? [It was] an unusual reaction… (Kylie, Low PRS) Interviewer: How did you find [the consultation]? Interviewee: Yeah, it was absolutely pleasant, very interesting, very positive I thought. (Kylie, Low PRS) Dealing with uncertainty Well there’s no concrete answers in the whole word. I mean I don’t think it’s a problem as far as I’m concerned. You just have to live with what is. (Mia, Low PRS) Removing

I thought ‘well if this shows that there is no connection, that could be awkward.’

self-doubt

The fact that there was some was- sounds ridiculous but satisfying because

and denial

there’s always that self-doubt, you're always thinking ‘is this something that is real or is this something that is fictional? (James, Intermediate PRS) Interviewee: I guess I was hoping that I didn’t have the markers. Interviewer: Why is that? Interviewee: I was hoping I didn’t really have bipolar maybe… but I have to accept that I’ve got it and that’s making me accept it more (Dianna, Intermediate PRS).

Sharing the

I think it’s good [to receive the PRS] in person because it makes you reflect on the

experience

condition and maybe the stressful events that you’ve been through… it’s good to have someone who seems very supportive and goes through things really well, so I think it’s important to have someone like a genetic counsellor. (Phoebe, Intermediate PRS) I told my wife and my mother. I think I’ve told a few friends and that sort of stuff just because, you know a lot of people have seen me in really dark places so it’s nice to just let them know that there is a potential reason for it. Or a real reason for it rather than you know… as we say ‘pathologising’. (James, Intermediate PRS)

Reinforcing management

I think it was probably a warning to me to not be too complacent… to keep your eye out for bipolar symptoms, even though life seems to be going well, a little 26

strategies

more maybe than I have been. (Daisy, High PRS) It’s another proof to my brain that I must stick to the program and don’t try and deviate. (Todd, Low PRS)

Table 4: Participants’ understanding and interpretation of the results and the grey area Concept

Quotation/s

A lot remains

PRS does not account for environmental or currently unknown genetic factors

unknown

My understanding is that the test identifies a number of different genetic markers for the increased probability of developing BD. It’s not a predictive test because there’s a lot of other factors, other than those genetic markers. Presumably over time the tests could become more accurate, because there might be genes that are not recognized at the moment that might be more important and more conclusive. (Charles, High PRS) Confusion It was basically the graph that I didn’t understand. I’m naturally an absolute dumbo when it comes to maths. I’m absolutely hopeless and I look at a graph and I just glaze over. (Alice, High PRS) I had to sit down and re-read [the handouts] and think about it to get it again. (Liam, High PRS)

Understanding Alleles may be inherited from unaffected parent/s inheritance

I wondered whether it might have been you know, latent somewhere maybe even in my father’s line even though there’s no known mental health problems in my father’s family at all. (Daisy, High PRS) Interpreting results that are discordant with family history Because I’ve got three kids with bipolar, I’ve got bipolar…I’ve been always assuming that there was a really strong genetic link, which it might still be from their dad as well…there are other things going on obviously. That’s the grey area. (Kylie, Low PRS)

Recall of PRS

Not only was I higher in terms of vulnerability than the general population,

in relative

which you would expect, I was actually more vulnerable than the majority of

terms

the bipolar population. (Daisy, High PRS)

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Table 5. Perceived benefits of future genetic testing for BD Perceived Benefit

Quotation/s

Early diagnosis

I had a horrible period, probably 10 years of ‘what exactly is the problem?’… I think [genetic testing] would be useful for cutting through that diagnostic delay (Daisy, High PRS)

Diagnostic clarification

That hell of 18 months that I went through [on Selective Serotonin

and appropriate

Reuptake Inhibitors (SSRIs)] … It would be nice if somebody was

treatment

able to do a blood test and say, ‘Oh there’s a good chance this is bipolar not unipolar, quick let’s put you on stuff that will work for bipolar and don't worry about these bloody SSRIs (Mia, Low PRS)

Validation of illness and reduced self-blame

I think it’s important that people don’t struggle through and think, like I did, that it’s all their fault, it’s something they’ve done or something they’ve thought or something they’ve eaten (Alice, High PRS)

Improved awareness

If you’re aware – an example would be when my youngest son got sick and he got suicidal… straight away I picked up what it was… both my older children often say that he’d be dead if it wasn’t for the fact that I knew what it was. (Kylie, Low PRS)

Assistance in making informed decisions

I guess knowing the risks involved would help a lot of people make decisions… I guess if I knew before my son was born that I carried the genes for bipolar disorder, my wife and I would have thought very, very seriously about having a child. (Mark, Decliner)

Possibility for tailored medication

I’ve probably tried 25 medications, and some had really diabolical side effects… It would be great to be able to [understand the problems in DNA and] tailor medication rather than just trial and error which is the way it’s done now. (James, Intermediate PRS)

Improved stigma

I think if there’s something on a piece of paper that you can show people, like ‘look I have this physical problem here in my genes’, that I imagine would go a long way to help with the stigma because, you know, people are generally like ‘it’s just in your brain’. (Lucas, High PRS)

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Table 6. Perceived risks associated with future genetic testing for BD Risk

Quotation/s

Insurance

Insurance companies might not insure you because there’s a higher risk of

discrimination

suicide… I think that probably needs to be addressed on a legal basis. (Mark, Decliner)

Genetic determinism

When I was diagnosed bipolar and the whole 'this is a genetically-based illness' idea was presented to me, I completely lost hope because I can’t control my genes… People won’t think that recovery is possible because genes aren’t going to change. (Cate, Decliner)

Increased anxiety

For somebody without bipolar the test could be more disturbing and could

when BD may

be quite upsetting in the context of something that might not actually

never eventuate

happen to them. (Chris, High PRS)

A self-fulfilling prophecy Pressure not to have children Thinking you are immune if deemed

If you have a strong marker, does that mean that you will go looking for it? Because you see what you look for. (Kylie, Low PRS) If it’s known that you are above a certain vulnerability could there be a pressure to not have children? (Daisy, High PRS) You might think if you get a low score that you’re not going to get it, then you might still. (Laura, High PRS).

low-risk Increased stigma

It means that [people with BD] are seen as a diseased individual that is genetically malformed in some way… that perception of ‘you’re not like us’… it’s sort of it really reinforces that 'freak, can’t be understood, broken' kind of perception. (Cate, Decliner)

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Acknowledgements: We are very grateful to the individuals who participated in this study. Bettina Meiser is supported by a Senior Research Fellowship Level B from the National Health and Medical Research Council (ID 1078523). Initial recruitment and genotyping of the sample was supported by the Australian National Health and Medical Research Council (Program Grant 1037196, PI: Philip B. Mitchell and Project Grant 1066177, PI: Janice M. Fullerton), with support from the Janette Mary O’Neil Research Fellowship (to JMF). The study was supported by the University of New South Wales, Sydney.

Author Statement Contributors: We strongly believe that authorship is appropriate for all of the ten authors listed, on the basis of their contribution and the complexity of the study. Sophie Putt, Bettina Meiser, and Tatiane Yanes led the design and conduct of this work, and all authors contributed to the study concept and design. Sophie Putt, Bettina Meiser, Tatiane Yanes and Rajneesh Kaur were responsible for data integrity and analyses for the study. Sophie Putt was responsible for qualitative data acquisition from interviews. Sophie Putt, Bettina Meiser, Tatiane Yanes and Kristine BarlowStewart and Holly Peay developed the educational brochure for participants to facilitate decisionmaking about whether to learning their polygenic risk score, with significant feedback from Janice Fullerton, Peter Schofield and Phil Mitchell. Sophie Putt, Bettina Meiser, Tatiane Yanes Kristine Barlow-Stewart, Holly Peay, Peter Schofield and Philip Mitchell developed the consultation guide for the test result disclosure session. Janice Fullerton and Claudio Toma calculated the polygenic risk scores and developed their graphical representation for inclusion in the materials returned to participants. Sophie Putt, Bettina Meiser, Tatiane Yanes and Rajneesh Kaur were responsible for the qualitative analyses and interpretation. Sophie Putt drafted the manuscript. All authors contributed to the critical revision of the manuscript for intellectual content. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Role of Funding Source: Bettina Meiser is supported by a Senior Research Fellowship Level B from the National Health and Medical Research Council (ID 1078523). Initial recruitment and genotyping of the sample was supported by the Australian National Health and Medical Research Council (Program Grant 1037196, PI: Philip B. Mitchell and Project Grant 1066177, PI: Janice M. 30

Fullerton), with support from the Janette Mary O’Neil Research Fellowship (to JMF). The study was supported by the University of New South Wales, Sydney.

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