Twin studies allow us to determine the degree to which traits and disorders are heritable within specific populations. Most of these studies use volunteer registries of twins, and most are in North America, Europe, and Australia (Boomsma et al., Reference Boomsma, Busjahn and Peltonen2002). However, it is not known how far these findings are generalizable and applicable to developing countries, and application of twin study methods for cross-cultural comparisons is limited. Population-based registries are rare, even in the West (Boomsma et al., Reference Boomsma, Busjahn and Peltonen2002). The uniqueness of the Sri Lankan Twin Registry (SLTR) lies in the fact of it being the first in the developing world (Sumathipala et al., Reference Sumathipala, Fernando, Siribaddana, Abeysingha, Jayasekare, Dissanayake and De Silva2000a, Reference Sumathipala, Siribaddana, De Silva, Fernando, Abeysinghe, Dayaratne and Hotopf2002). It is still one of the few large-scale, functioning population-based registries in the developing world (Van Dongen et al., Reference Van Dongen, Slagboom, Draisma, Martin and Boomsma2012).
Brief History of SLTR
The development of a twin registry in Sri Lanka was proposed and initiated by AS in 1997 (Sumathipala et al., Reference Sumathipala, Siribaddana, De Silva, Fernando, Abeysinghe, Dayaratne and Hotopf2002). The objective was to establish a nation-wide twin registry, starting initially as a volunteer registry, and subsequent development of a population-based registry. It was envisaged that it would become a platform for a multidisciplinary approach toward twin research in the low- and middle-income country (LMIC) context. The evolutionary process of the SLTR has been reported previously (Siribaddana et al., Reference Siribaddana, Hewege, Siriwardena, Athukorale, Sumathipala and Hotopf2006; Sumathipala et al., Reference Sumathipala, Fernando, Siribaddana, Abeysingha, Jayasekare, Dissanayake and De Silva2000a, Reference Sumathipala, Siribaddana, De Silva, Fernando, Abeysinghe, Dayaratne and Hotopf2002).
Several strategies for twin recruitment were employed; initial enrolling of volunteer twins through media campaigns was followed by tracing of twins through birth registration records and conduction of population-based recruitment (Sumathipala et al., Reference Sumathipala, Fernando, Siribaddana, Abeysingha, Jayasekare, Dissanayake and De Silva2000a, Reference Sumathipala, Siribaddana, De Silva, Abeysinghe, Sivayogam and Fernando2001, Reference Sumathipala, Siribaddana, Abeysinghe, De Silva, Fernando, Dayaratne and Hotopf2003). Therefore, the SLTR has mainly a volunteer cohort and a population-based cohort (Siribaddana et al., Reference Siribaddana, Hewege, Siriwardena, Athukorale, Sumathipala and Hotopf2006; Sumathipala et al., Reference Sumathipala, Fernando, Siribaddana, Abeysingha, Jayasekare, Dissanayake and De Silva2000a, Reference Sumathipala, Siribaddana, De Silva, Fernando, Abeysinghe, Dayaratne and Hotopf2002).
The SLTR is a sustainable program, established through a strategic, multidisciplinary partnership between the Institute for Research and Development (IRD) and Institute of Psychiatry, King's College London. This initiative was mainly built upon competitive and substantial funding from the Wellcome Trust.
Current Status of the SLTR
Volunteer Cohort
This was established by recruiting twins through a national newspaper advertising campaign, as an island-wide registry. The SLTR volunteer cohort has 14,120 twins (7,060 pairs) and 119 sets of triplets registered. The age range is from 1 to 85 years. However, 72% of twins are less than 30 years of age. It comprises of 2,386 male–male, 2,919 female–female, and 1,728 male–female twin pairs. Gender details are not available for 27 twin pairs. Triplets comprise of 23 all male sets, 36 all female sets, and 59 mixed gender sets. Details are missing for 1 set. Zygosity identification has not been carried out for the volunteer cohort. Further details of gender and age groups are given in Table 1.
TABLE 1 Age Group Description of Volunteer Twin Cohort
Population-Based Cohort
This is confined only to the Colombo district. The SLTR population-based cohort has 19,040 twins (9,520 pairs) and 89 sets of triplets registered. The age ranges from 6 to 96. Twins comprise of 3,052 male–male, 3,282 female–female, and 2,488 male–female pairs. Gender details are missing in 698 pairs. Triplets comprise 25 sets of all males, 39 sets of all females, and the rest of mixed gender. Further details on gender and age groups are also given in the Table 2. Zygosity was ascertained only on twins who participated in the Colombo Twin and Singleton Study (CoTaSS 1). There were 2,274 dizygotic pairs and 1,691 monozygotic pairs; information was missing for 30 (total 3,995). Details are given in Table 3. The overlap between the island-wide volunteer cohort and population-based Colombo district cohort is 334 twins.
TABLE 2 Age Group Description of Population-Based Twin Cohort
TABLE 3 Zygosity and Age Group Breakdown of Twin Participants in CoTaSS 1
Zygosity Assessment
Translation, adaptation, and preliminary validation of a zygosity determination questionnaire by Ooki et al. (Reference Ooki, Yamada and Asaka1993) were undertaken at the outset (Sumathipala et al., Reference Sumathipala, Silva, Siribaddana, Abeysinghe and Fernando2000b). However, this questionnaire was not validated against the gold standard using genetic markers. We are in the process of completing this work, utilizing DNA extracted from buccal cells.
Specific Research Based on the Population Cohort
The CoTaSS 1
The main objectives of this study were to: (1) identify a representative population-based twin sample in Colombo district of Sri Lanka; (2) describe the prevalence of psychiatric disorders within the twin sample and a parallel singleton sample which is a unique feature of this specific study; (3) estimate the heritability of common mental disorders within the twin study; (4) explore the interplay between genetic and environmental influences on psychiatric disorders. To date, seven papers have been published using data from CoTaSS 1 (Ball et al., Reference Ball, Sumathipala, Siribaddana, Kovas, Glozier, McGuffin and Hotopf2009, Reference Ball, Siribaddana, Sumathipala, Kovas, Glozier, McGuffin and Hotopf2010a, Reference Ball, Siribaddana, Kovas, Glozier, McGuffin, Sumathipala and Hotopf2010b, Reference Ball, Sumathipala, Siribaddana, Kovas, Glozier, McGuffin and Hotopf2010c, Reference Ball, Siribaddana, Sumathipala, Kovas, Glozier, Frühling and Hotopf2011; Siribaddana et al., Reference Siribaddana, Ball, Hewage, Glozier, Kovas, Dayaratne and Hotopf2008; Zavos et al., in press). The key findings to date are summarized below.
Prevalence of Psychiatric Disorders
One of the main aims of CoTaSS 1 was to establish the prevalence of psychiatric problems in a representative sample of twins and singletons from the Colombo district of Sri Lanka. Findings for depression indicate that the prevalence is lower than in many Western countries, although symptom patterns were similar. A significant interaction was observed between gender and risk factors such as low education and low access to material resources (Ball et al., Reference Ball, Siribaddana, Sumathipala, Kovas, Glozier, McGuffin and Hotopf2010a; Siribaddana et al., Reference Siribaddana, Ball, Hewage, Glozier, Kovas, Dayaratne and Hotopf2008). These risk factors were strongly associated with depression in men.
A quarter of the sample had abnormal fatigue (Ball et al., Reference Ball, Sumathipala, Siribaddana, Kovas, Glozier, McGuffin and Hotopf2010c). The associated risk exposures were similar to those of depression and included early school leaving, poor standard of living, life events over the past 12 months, and parental neglect. Prevalence of substance use problems, including tobacco use, varied substantially by gender (Zavos et al., 2012).
Heritability of Common Mental Disorders
Overall, a very similar pattern of heritability has been shown in the current sample compared with results from twin studies in western countries for depression, fatigue, and tobacco use (Ball et al., Reference Ball, Sumathipala, Siribaddana, Kovas, Glozier, McGuffin and Hotopf2009, Reference Zavos, Kovas, Ball, Ball, Siribaddana, Glozier and Rijsdijk2010c; Zavos et al., 2012). However, some differences were noted. For example, the heritability of a broad depression diagnosis was found to be significantly lower in men compared to women in this population, and this heritability was lower than most studies in Europe, Australia, and North America (Ball et al., Reference Ball, Sumathipala, Siribaddana, Kovas, Glozier, McGuffin and Hotopf2009).
Gene-Environment Interplay
We investigated a range of environmental exposures and their genetic or environmental contribution to depression and fatigue (Ball et al., Reference Ball, Siribaddana, Sumathipala, Kovas, Glozier, McGuffin and Hotopf2010a). Gene-environment correlation was evident for some of the measured environments. Early school leaving and standard of living showed environmentally mediated effects on depression in men. In women, life events were associated with depression partly through genetic pathways. For fatigue, there were environmentally mediated effects and strong suggestions of family-environmental influences.
Involving a parallel singleton sample allowed us to report current and lifetime prevalence rates of psychiatric disorders in Sri Lanka. Comparison with the twin sample suggested that prevalence rates in twins were representative of the wider population, once adjusted for factors such as age (Ball et al., Reference Ball, Siribaddana, Sumathipala, Kovas, Glozier, McGuffin and Hotopf2010a, Reference Zavos, Kovas, Ball, Ball, Siribaddana, Glozier and Rijsdijk2010b; Zavos et al., 2012).
CoTaSS Follow-Up Study (CoTaSS 2)
Previous research has provided evidence of an association between cardiovascular disease, diabetes, and depression (Katon et al., Reference Katon, Rutter, Lin, Ludman and Ciechanowshi2005). In the CoTaSS 2, we are exploring the prevalence and interrelationship of a number of key cardiovascular and metabolic risk markers (e.g., metabolic syndrome). Diabetes, heart disease, and depression have become significant public health priorities in Sri Lanka. Therefore, an investigation into the extent of overlapping genetic and environmental influences is a timely requirement.
The main aims of the CoTaSS 2 are: (1) estimating the prevalence of the component phenotypes which make up ‘metabolic syndrome’ in Sri Lanka; (2) investigating the genetic architecture of metabolic syndrome phenotypes, and estimate the extent to which phenotypic correlations are explained by shared genetic or environmental effects; (3) determining whether there is a significant etiological overlap between depression and the component phenotypes of metabolic syndrome.
The CoTaSS 2 study was initiated in May 2012, 5 years after the completion of the CoTaSS 1 study data collection. We have successfully managed to trace around 1,600 twins of baseline sample, and have completed 1,336 questionnaire interviews by mid-October 2012. The response rate is around 83%. Collection of biological material (blood) was started at a later stage and is currently in progress. Table 4 presents a summary comparison of CoTaSS 1 and 2 study attributes.
TABLE 4 Comparative Attributes of CoTASS 1 and CoTaSS 2
A sub-study within the CoTaSS 2 phase aims to evaluate the contribution of sleep and activity levels to the prevalence of metabolic syndrome and depression in Sri Lanka, using self-report and actigraphy. It is led by NG and will be the first study to determine population-based estimates of validated sleep parameters in a developing country (Stranges et al., Reference Stranges, Tigbe, Gómez-Olivé, Thorogood and Kandala2012).
Major Goals of the SLTR
We look to extend our current work beyond mental health, and interface between mental and physical health. Through the CoTaSS 2, we have obtained the necessary ethical clearance for biobanking DNA and serum/plasma. We intend to engage in epigenetic, genome-wide association, and candidate gene studies. Through these studies, we are looking to expand our horizons and extend our collaboration with the wider global twin research community. We look forward to working with the international twin research community in twin data harmonization. Gradual expansion of the existing Colombo-based registry to rest of the country is also being targeted.
Since inception, our strategic agenda has been to work toward a sustainable center of excellence in twin and genetic research in a LMIC through North–South collaboration. We thereby aim to expand the twin research program through multidisciplinary and cross-disciplinary approaches. Capacity building in relevant expertise is an integral part in our initiative.
In keeping with one of our primary targets set at the inception of SLTR, we have established a state-of-the-art genetic laboratory.
Ethics and Governance
The SLTR has huge potential as a unique resource due to its location, size, and design. However, as it is from a resource-poor country it could be vulnerable to exploitation for easy and cheap research. In order to protect the SLTR and its registrants, we followed carefully designed ethical and governance frameworks, which have been developed in parallel to SLTR (Sumathipala et al., Reference Sumathipala, Siribaddana, De Silva, Fernando, Abeysinghe, Dayaratne and Hotopf2002).
Initially, ethical clearance was obtained from ethics committees at the Faculty of Medicine, University of Colombo and the Institute of Psychiatry, London (Sumathipala et al., Reference Sumathipala, Fernando, Siribaddana, Abeysingha, Jayasekare, Dissanayake and De Silva2000a). For the CoTASS 1 study, ethical clearance was obtained from the Institute of Psychiatry, London, Sri Jayewardenepura University Ethics Committee, Sri Lanka, and also from the WHO's Ethics Committee (Siribaddana et al., Reference Siribaddana, Hewege, Siriwardena, Athukorale, Sumathipala and Hotopf2006). For the CoTaSS follow-up study and the biobank, ethical clearance was obtained from the Institute of Psychiatry, London, and the Sri Jayewardenepura University Ethics committee.
Specific National and Regional Issues
Cultural attitudes toward twins have not been specifically studied in Sri Lanka. Even though not systematically investigated or documented, there is indirect evidence of a negative attitude toward genetic research in Sri Lanka. There have been a few media reports on exporting genetic material, portrayed as an exploitation of Sri Lankan genetic heritage. Therefore, since the beginning of the SLTR, being sensitive to cultural and social challenges has been our credo. To this end, establishing the genetic lab was a major strategic accomplishment.
Public Engagement
Public engagements have been one of the core themes running through all of the work conducted at the IRD, which houses the twin registry as one of its main research programs. SLTR public engagement work includes publishing regular newsletters for twins, using the IRD trilingual journal to create awareness about twin research among the public, and a Wellcome Trust-funded 3-year project (Multiples Engage in Research through Culture — MERC) led by SS and AS.
Discussion
Scarcity of research capacity in LMIC has been well established (Patel, Reference Patel2007; Razzouk et al., Reference Razzouk, Sharan, Gallo, Gureje, Lamberte, Mari and Saxena2010; Siriwardhana et al., Reference Siriwardhana, Sumathipala, Siribaddana, Samaraweera, Dayaratne, Abeysinghe and Prince2011). However, the SLTR and the wider IRD initiative have showcased how successful North–South partnerships can overcome barriers to minimize the 10/90 divide (where 90% of global research funding targets the disease burden of only 10% of world population; Siriwardhana et al., Reference Siriwardhana, Sumathipala, Siribaddana, Samaraweera, Dayaratne, Abeysinghe and Prince2011). This is especially poignant considering the facts that twin research concept was novel to Sri Lankans, the existing scarcity of research funding and lack of local expertise in twin method. However, in a perfect example of North–South collaboration, support and expertise came from colleagues at King's College London to establish SLTR and ensure its sustenance.
Author Contributions
Authorships are given in descending order of seniority with the SLTR starting with AS.
Acknowledgments
We received three funding grants (060379/Z/00/Z, 069629/Z/02/Z, 093206/Z/10/Z) from the Wellcome Trust, United Kingdom, to support this work. SS, HB, and YK were employed full time for CoTaSS 1 and KJ and HZ (full-time) and SS, AA, GP, and DG (part-time) for CoTaSS 2. The sleep and activity substudy is funded by the Australian NHMRC (grant numbers 571421 and 566529). We would like to acknowledge all those who were actively involved since the inception of SLTR, including those who have been acknowledged in the previous publications. We would also like to acknowledge Chamali Jayasinghe, Maneesha Jayaweera, Nilanthi Priyadharshani, Mekala Narangoda, Janani Marasingha, Aruna Walisundara, Nadun Perera, Hansini Gamage, Vidath samarakkody, Udeni Samanmalie, T. Jeyakumar, and Dr. Patricia Zunszain for their contribution to CoTaSS 1 and 2. We would further like to acknowledge the IRD executive committee, other staff, and research assistants.
