Autism and perinatal epidemiology – Sven Sandin research group

We are investigating the underlying causes and factors influencing the risk of autism, preterm birth and related factors and diagnoses. Our approach is to use modern statistical and epidemiological methods to extract and synthesize information from large population-based databases, and to collect new data as needed. We work in close collaboration with universities mainly in the Nordic countries, the USA and Israel.

Our research

Today, there is a wealth of large databases describing the health and demographics of different populations. The availability of data alone, however, is not sufficient to understand the underlying causes and life course of common diseases and disorders. We apply modern statistical and epidemiological methods to extract and create new data and information from these data sources. To fully understand how the information can answer our various research questions, we need expertise from a spectrum of research disciplines. These include international experts in biostatistics, data science and data management, epidemiology, public health, clinical expertise, biology and genetics.

Publications

All publications from group members

Staff and contact

Group leader

All members of the group

Other people connected to the group

  • Zhong, Qiaofeng

Visiting address

Karolinska Institutet, Department of Medical Epidemiology and Biostatistics, Nobels väg 12A, Stockholm, 171 77, Sweden

Postal address

Karolinska Institutet, Department of Medical Epidemiology and Biostatistics, PO Box 281, Stockholm, 171 77, Sweden

PAGES

"PAGES" is an abbreviation for “Population-Based Autism Genetics and Environmental Study”, which illustrates that it is not only a single gene that leads to an increased risk of autism but a complex pattern of several different genes and environmental factors, which in combination creates increased vulnerability. The PAGES study is a collaboration between Karolinska Institutet and the Seaver Autism Center for Research and Treatment at the Icahn School of Medicine in New York, USA, one of the world's leading research institutes for autism research. Most of the funding comes from the USA, from national research grants, but also from donations from people who want to help to promote research on autism spectrum states.

What is Autism Spectrum Disorder?

ASD is a disorder that affects at least 1% of all children and adolescents in Sweden. The first signs of ASD are typically seen during early pre-school age and are characterized by communication problems and difficulty to interpret and understand other people's thoughts and feelings.
Both genes and the environment are important causes for ASD. Research from our group using collected genetic material has previously shown that genes are of importance. There are most likely many genes involved in the development of autism and these probably affect the production and absorption of important proteins in the brain cells. An increased sensitivity in these systems may increase the risk of ASD, especially in combination with external stresses and environmental factors. More information about ASD can be found here on the 1177 Care Advisory website or on the Autism & Asperger Federation website.

Study information

About 1 in 100 are diagnosed with ASD at some point in life. It has long been assumed that ASD is inherited in the family. In recent years, family studies using knowledge about the genetic relationship between different family members have shown that the variation in risk that can be explained by genetic factors is about 80% (this measure is commonly referred to as "heritability"). Previously collected genetic material (blood and saliva samples) from Karolinska Institutet has also played an important role. We have also been able to demonstrate the high heredity through genetic data.

The causes of autism spectrum states appear to be genetically complex. A large number of genes, each with only a modest effect individually, when acting together can cause a vulnerability and can, together with environmental factors, trigger the ASD.

In recent years, the techniques for genetic studies of complex diseases have developed rapidly. Through genome-wide association studies (GWAS), several vulnerabilities have been identified for type 1 and 2 diabetes, rheumatism, cardiovascular disease, prostate and breast cancer, for example. This has been of great importance for understanding the mechanisms of these diseases. For ASD, several studies have been conducted with promising results that form the basis for further studies, but the findings of these studies have not been possible to be replicated. To move the research in psychiatric genetics forward and close the gaps in knowledge, large and well-defined studies are needed. Using the large Swedish state-of-the-art registers of the Swedish government National Board of Health and Welfare, we have a unique opportunity to achieve these goals.

Approach

In our study we invite people born in Sweden and who have been diagnosed with ASD at some point during their lives. When we invite people to participate in the study, we only have information that the person has been diagnosed with autism at some point in life. We have no data from medical records, current health or any other diagnoses. Information about an autism diagnosis comes from the Patient Register, held by the National Board of Health and Welfare. This is a health register for both somatic and psychiatric diagnoses and contains all psychiatric care facilities in Sweden from 1973 and onwards, and to a varying degree, also includes out-patient care. Only clinical specialists may assign an autism diagnosis that is stored in the Patient Register.

The participants are invited through an information letter followed by a telephone call from one of our research nurses. Since people with autism sometimes can be difficult to reach, we try to work with relatives, close relatives and treatment staff when needed. Individuals with autism may exhibit a varying degree of symptoms. For the most severely affected, we have developed a picture support in addition to the information sent to the invited persons, which explains the examination procedure in a simple way, thus increasing the chance that everyone will be able to decide if they want to participate in the study or not.

If the person decides to participate, we first require a signed consent that the person wishes to participate in the study. The person is then asked to give a saliva sample. Sometimes people may have problems with a dry mouth, but we only ask for a small amount of saliva, about 2 ml. If the participant so wishes, it is possible to give a blood sample instead of a saliva sample. All participants are also asked if we can obtain information about them from other national registries, such as the Medical Birth Register, the National Patient Registry, the Multi-Generation Register and the Prescription Register. The purpose is to enable linkage between genetic data and other characteristics of the participants. Examples of such information are the age of the mother and the father when the person was born. The age of parents has been shown to be of importance for developing ASD in several research studies, and it is therefore important to be able to study whether genetic markers can provide any information to better understand these relationships.

When data collection is complete and all analyzes are complete, comparisons will be made to investigate whether genetic variants appear to be more vulnerable to the development of ASD. The group of people with ASD will be compared with control persons who do not have an ASD diagnosis. Processing of the data will be performed without identifying individual persons.

Significance and purpose

The PAGES study is unique in its kind as it is a national population-based study. This means that we request information from all living in a certain geographical area. Using this approach we can avoid many problems when interpreting research findings that may occur if a smaller group of individuals is included. Our research group has experience of conducting similar studies on Obsessive-Compulsive Disorder (EGOs), Schizophrenia (BROAD study) and bipolar disorder (STANLEY study). Since ASD may share certain genetic causative factors with schizophrenia and other psychotic diseases, the overall results of these studies can provide important information and increased understanding of underlying factors.

What is happening in the study?

In October 2018, we will send out the first study invitations. We will then continue recruitment for at least three years. We will update our website continuously to inform about how the study develops and when we publish research findings that are relevant to the study or that use data that our participants have contributed.

In February 2019, we have published a new scientific article in Nature. In this study where genetic data from PAGES were included, for the first time, 12 common gene variants that increase the risk of autism were discovered.

What's the importance of participating in the study?

Participating in a scientific study does not always directly benefit the person involved but the participation can be of major significance to other people who suffer from the same disability or disease, both in our own generation and in future generations, in Sweden as well as internationally. In particular, the understanding of the causes of these conditions can help prevent both the development of ill health and disease and improve treatment.

Participation in the study is entirely voluntary. The participant may, at any time, suspend his participation and by law (GDPR) request that all collected information be deleted.

What happens to the sample?

Each person participating in the study gives a saliva sample of about 2 ml. The samples are sent to the Karolinska Institutet Biobank where DNA (legacy) is extracted. A subset of the sample is then sent to a genetic laboratory where genetic analyzes are performed. When data collection is complete and all analyzes are complete, comparisons will be made to investigate whether genetic variants appear to be more vulnerable to the development of ASD. Processing of the data will be performed without identifying individuals. Results will always be reported at group level.

Biobank

The samples will be stored in Karolinska Institutet biobank. Since 2003, there has been a Swedish law on biobanks, the Biobanks Act (BbL 2002: 297), which means that the participant will get information about and approve that samples are stored in a biobank and what they may be used for. The person who has provided a sample also must decide on how the samples may be used in the future. You are always entitled to change your decision at any time.

Research and Ethics

According to Swedish law (Ethics Examination Act - Law 2003: 460) on ethics testing of human-related research), all research projects must be approved by a research ethics committee that assesses whether the project is important and whether it can be implemented without compromising the integrity of the study participant. This study has received such approval by the Regional Ethics Vetting Board in Stockholm. All personal data and samples are protected.

Saved samples are stored with unique codes so that unauthorized users cannot access them. Personal data is protected under the Data Protection Regulation (GDPR), which applies throughout the EU. You can request in writing to find out what data is registered about yourself. Once a year you are is entitled to order such an excerpt without charge. You also have the right to change information about yourself that is incorrect or incorrectly processed.

Responsible for the data register in the study is Karolinska Institutet, 171 77 Stockholm, tel. 08-524 800 00. Head of the study is research leader Sven Sandin, tel. 08-524 861 22 and Professor Christina Hultman; both belonging to the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet Solna.

Study personnel

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Sven Sandin

Statistician
+46852486122
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Karin Dellenvall

Research Nurse
+46852487427

Publications

The information and data provided by our study participants have already resulted in a number of scientific papers published in highly ranked international scientific journals. See the list below for some examples. All these studies are available to the general public so anyone can read them, so called open access. Naturally there is no information about individuals reported in the papers, but all information is reported on a group level.

Identification of common genetic risk variants for autism spectrum disorder.
Grove J, Ripke S, Als TD, Mattheisen M, Walters RK, Won H, et al
Nat. Genet. 2019 03;51(3):431-444

The Heritability of Autism Spectrum Disorder.
Sandin S, Lichtenstein P, Kuja-Halkola R, Hultman C, Larsson H, Reichenberg A
JAMA 2017 09;318(12):1182-1184

Most genetic risk for autism resides with common variation.
Gaugler T, Klei L, Sanders SJ, Bodea CA, Goldberg AP, Lee AB, et al
Nat. Genet. 2014 Aug;46(8):881-5

Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci.
Sanders SJ, He X, Willsey AJ, Ercan-Sencicek AG, Samocha KE, Cicek AE, et al
Neuron 2015 Sep;87(6):1215-1233

Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.
Lim ET, Uddin M, De Rubeis S, Chan Y, Kamumbu AS, Zhang X, et al
Nat. Neurosci. 2017 09;20(9):1217-1224

Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia.

Mol Autism 2017 ;8():21

Synaptic, transcriptional and chromatin genes disrupted in autism.
De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, et al
Nature 2014 Nov;515(7526):209-15

Common risk variants identified in autism spectrum disorder. Grove J, Ripke S, Als TD, et al. bioRxiv 2017;:224774.

ASD and ADHD have a similar burden of rare protein-truncating variants. Satterstrom FK, Walters RK, Singh T, et al. bioRxiv 2018;:277707.

Analysis of shared heritability in common disorders of the brain.
Anttila V, Bulik-Sullivan B, Finucane HK, Walters RK, Bras J, et al
Science 2018 06;360(6395):

Women's lifestyle and health

Project description

Oral contraceptives, use of hormone replacement therapy, dietary habits and other lifestyle factors affect the risk for cancer, cardiovascular diseases and other chronic diseases in young women. Starting in 1991, a comprehensive questionnaire was mailed to 96,000 Swedish women aged 30-49 years.

Approximately 50,000 completed questionnaires were returned providing detailed information on a wide range of lifestyle factors with a focus on oral contraceptive use, diet, UV light exposure, reproductive factors and familial occurrence of cancer. This study is strictly coordinated with a similar study among 60,000 young women in Norway; apart from the dietary component, the questionnaires are identical and joint analyses are planned. In 2003 a second questionnaire was sent to all women to update information on lifestyle changes as well as to access psychiatric morbidity. Currently analysis is ongoing for several lifestyle factors and cancers of the breast, ovarium, endometrial, colorectal, skin, skin melanoma, lymphomas, as well as cardiovascular outcomes (myocardial infarction, haemorrhagic and ischaemic stroke), psychiatric diseases, sleeping disorders and overall mortality.

Several analyses are being performed on different exposures, such as oral contraceptives, BMI, changes in body size and shape, UV radiation exposure, alcohol consumption, smoking, and risk of different cancer sites and overall mortality. The data management and analysis of the follow-up questionnaire is ongoing.

Project period: 1991-ongoing
Main financing: Swedish Cancer Society, Swedish Research Council, Pharmaceutical companies (for the initiation of the study)

Project leader

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Sven Sandin

Statistician
+46852486122

Project collaborators

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Elisabete Weiderpass Vainio

Professor
+46852482510
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Hans-Olov Adami

Professor Emeritus/Emerita

Partners

  • Department of Medical Epidemiology and Biostatistics - KI: Hans-Olov Adami (co-PI), Marie Löf (nutritionist), Sven Sandin (Statistician), Pouran Almstedt (data base manager)
  • University of Tromsø, Norway: Eiliv Lund, Merethe Kumle, Inger Gram, Merethe Kumle, and Tonje Braaten (Tromsø, Norway)
  • Oslo University, Department of Statistics: Marit Veierod
  • University of Auckland, New Zealand: Prof. Robert Scragg (Head of dept. of Epidemiology) and Alistair Stewart (Senior statistician)
  • University of Birmingham, UK : Prof. Maurice Zeegers
  • University of Queensland, Australia : Prof. Gita Mishra

Collaborators

Marie Löf, professor
Pouran Almstedt, database manager

Publications

Fruit and vegetable intake and risk of breast cancer by hormone receptor status.
Jung S, Spiegelman D, Baglietto L, Bernstein L, Boggs D, van den Brandt P, et al
J. Natl. Cancer Inst. 2013 Feb;105(3):219-36

InterLACE: A New International Collaboration for a Life Course Approach to Women's Reproductive Health and Chronic Disease Events.
Mishra G, Anderson D, Schoenaker D, Adami H, Avis N, Brown D, et al
Maturitas 2013 Mar;74(3):235-40

Dimensions of psychotic experiences among women in the general population.
Therman S, Suvisaari J, Hultman CM
Int J Methods Psychiatr Res 2014 Mar;23(1):62-8

A pooled analysis of waist circumference and mortality in 650,000 adults.
Cerhan JR, Moore SC, Jacobs EJ, Kitahara CM, Rosenberg PS, Adami HO, et al
Mayo Clin. Proc. 2014 Mar;89(3):335-45

Association between class III obesity (BMI of 40-59 kg/m2) and mortality: a pooled analysis of 20 prospective studies.
Kitahara CM, Flint AJ, Berrington de Gonzalez A, Bernstein L, Brotzman M, MacInnis RJ, et al
PLoS Med. 2014 Jul;11(7):e1001673

Host characteristics, sun exposure, indoor tanning and risk of squamous cell carcinoma of the skin.
Veierød MB, Couto E, Lund E, Adami HO, Weiderpass E
Int. J. Cancer 2014 Jul;135(2):413-22

Endometrial cancer in relation to coffee, tea, and caffeine consumption: a prospective cohort study among middle-aged women in Sweden.
Weiderpass E, Sandin S, Lof M, Oh JK, Inoue M, Shimazu T, et al
Nutr Cancer 2014 ;66(7):1132-43

Body size and multiple myeloma mortality: a pooled analysis of 20 prospective studies.
Teras LR, Kitahara CM, Birmann BM, Hartge PA, Wang SS, Robien K, et al
Br. J. Haematol. 2014 Sep;166(5):667-76

Intrauterine devices and endometrial cancer risk: a pooled analysis of the Epidemiology of Endometrial Cancer Consortium.
Felix AS, Gaudet MM, La Vecchia C, Nagle CM, Shu XO, Weiderpass E, et al
Int. J. Cancer 2015 Mar;136(5):E410-22

Infertility and incident endometrial cancer risk: a pooled analysis from the epidemiology of endometrial cancer consortium (E2C2).
Yang HP, Cook LS, Weiderpass E, Adami HO, Anderson KE, Cai H, et al
Br. J. Cancer 2015 Mar;112(5):925-33

Adherence to the healthy Nordic food index, dietary composition, and lifestyle among Swedish women.
Roswall N, Eriksson U, Sandin S, Löf M, Olsen A, Skeie G, et al
Food Nutr Res 2015 ;59():26336

No Association between Adherence to a Healthy Nordic Food Index and Colorectal Cancer: Results from a Swedish Cohort Study.
Roswall N, Li Y, Kyrø C, Sandin S, Löf M, Adami HO, et al
Cancer Epidemiol. Biomarkers Prev. 2015 Apr;24(4):755-7

Anthropometry and head and neck cancer:a pooled analysis of cohort data.
Gaudet MM, Kitahara CM, Newton CC, Bernstein L, Reynolds P, Weiderpass E, et al
Int J Epidemiol 2015 Apr;44(2):673-81

Adherence to a healthy Nordic food index and breast cancer risk: results from a Swedish cohort study.
Li Y, Roswall N, Sandin S, Ström P, Adami HO, Weiderpass E
Cancer Causes Control 2015 Jun;26(6):893-902

Adherence to the healthy Nordic food index and total and cause-specific mortality among Swedish women.
Roswall N, Sandin S, Löf M, Skeie G, Olsen A, Adami HO, et al
Eur. J. Epidemiol. 2015 Jun;30(6):509-17

Leisure time physical activity and mortality: a detailed pooled analysis of the dose-response relationship.
Arem H, Moore SC, Patel A, Hartge P, Berrington de Gonzalez A, Visvanathan K, et al
JAMA Intern Med 2015 Jun;175(6):959-67

Prospective study of coffee consumption and all-cause, cancer, and cardiovascular mortality in Swedish women.
Löf M, Sandin S, Yin L, Adami HO, Weiderpass E
Eur. J. Epidemiol. 2015 Sep;30(9):1027-34

Prospective study of dietary inflammatory index and risk of breast cancer in Swedish women.
Shivappa N, Sandin S, Löf M, Hébert JR, Adami HO, Weiderpass E
Br. J. Cancer 2015 Sep;113(7):1099-103

No association between adherence to the healthy Nordic food index and cardiovascular disease amongst Swedish women: a cohort study.
Roswall N, Sandin S, Scragg R, Löf M, Skeie G, Olsen A, et al
J. Intern. Med. 2015 Nov;278(5):531-41

Prospective study of breast cancer in relation to coffee, tea and caffeine in Sweden.
Oh JK, Sandin S, Ström P, Löf M, Adami HO, Weiderpass E
Int. J. Cancer 2015 Oct;137(8):1979-89

Central adiposity, obesity during early adulthood, and pancreatic cancer mortality in a pooled analysis of cohort studies.
Genkinger JM, Kitahara CM, Bernstein L, Berrington de Gonzalez A, Brotzman M, Elena JW, et al
Ann. Oncol. 2015 Nov;26(11):2257-66

Alcohol consumption, body mass index and breast cancer risk by hormone receptor status: Women' Lifestyle and Health Study.
Shin A, Sandin S, Lof M, Margolis KL, Kim K, Couto E, et al
BMC Cancer 2015 Nov;15():881

Mediterranean and Nordic diet scores and long-term changes in body weight and waist circumference: results from a large cohort study.
Li Y, Roswall N, Ström P, Sandin S, Adami HO, Weiderpass E
Br. J. Nutr. 2015 Dec;114(12):2093-102

Anthropometric Factors and Thyroid Cancer Risk by Histological Subtype: Pooled Analysis of 22 Prospective Studies.
Kitahara C, McCullough M, Franceschi S, Rinaldi S, Wolk A, Neta G, et al
Thyroid 2016 02;26(2):306-18

Prospective Study of Dietary Phytoestrogen Intake and the Risk of Colorectal Cancer.
Hedelin M, Löf M, Sandin S, Adami H, Weiderpass E
Nutr Cancer 2016 ;68(3):388-95

Alcohol consumption and breast cancer risk by estrogen receptor status: in a pooled analysis of 20 studies.
Jung S, Wang M, Anderson K, Baglietto L, Bergkvist L, Bernstein L, et al
Int J Epidemiol 2016 06;45(3):916-28

Association of Leisure-Time Physical Activity With Risk of 26 Types of Cancer in 1.44 Million Adults.
Moore S, Lee I, Weiderpass E, Campbell P, Sampson J, Kitahara C, et al
JAMA Intern Med 2016 06;176(6):816-25

International pooled study on diet and bladder cancer: the bladder cancer, epidemiology and nutritional determinants (BLEND) study: design and baseline characteristics.
Goossens ME, Isa F, Brinkman M, Mak D, Reulen R, Wesselius A, et al
Arch Public Health 2016 ;74():30

Development and External Validation of a Melanoma Risk Prediction Model Based on Self-assessed Risk Factors.
Vuong K, Armstrong BK, Weiderpass E, Lund E, Adami HO, Veierod MB, et al
JAMA Dermatol 2016 08;152(8):889-96

Ovarian Cancer Risk Factors by Histologic Subtype: An Analysis From the Ovarian Cancer Cohort Consortium.
Wentzensen N, Poole EM, Trabert B, White E, Arslan AA, Patel AV, et al
J. Clin. Oncol. 2016 08;34(24):2888-98

The InterLACE study: Design, data harmonization and characteristics across 20 studies on women's health.
Mishra GD, Chung HF, Pandeya N, Dobson AJ, Jones L, Avis NE, et al
Maturitas 2016 Oct;92():176-185

Alcohol consumption over time and mortality in the Swedish Women's Lifestyle and Health cohort.
Licaj I, Sandin S, Skeie G, Adami HO, Roswall N, Weiderpass E
BMJ Open 2016 11;6(11):e012862

Changes in body mass index and waist circumference and concurrent mortality among Swedish women.
Roswall N, Li Y, Sandin S, Ström P, Adami HO, Weiderpass E
Obesity (Silver Spring) 2017 01;25(1):215-222

Determinants of long-term weight change among middle-aged Swedish women.
El Reda D, Ström P, Sandin S, Oh JK, Adami HO, Löf M, et al
Obesity (Silver Spring) 2017 02;25(2):476-485

Early menarche, nulliparity and the risk for premature and early natural menopause.
Mishra GD, Pandeya N, Dobson AJ, Chung HF, Anderson D, Kuh D, et al
Hum. Reprod. 2017 03;32(3):679-686

Body Size Indicators and Risk of Gallbladder Cancer: Pooled Analysis of Individual-Level Data from 19 Prospective Cohort Studies.
Campbell PT, Newton CC, Kitahara CM, Patel AV, Hartge P, Koshiol J, et al
Cancer Epidemiol. Biomarkers Prev. 2017 04;26(4):597-606

Cohort Profile: The Swedish Women's Lifestyle and Health cohort.
Roswall N, Sandin S, Adami HO, Weiderpass E
Int J Epidemiol 2017 04;46(2):e8

Breastfeeding and Endometrial Cancer Risk: An Analysis From the Epidemiology of Endometrial Cancer Consortium.
Jordan SJ, Na R, Johnatty SE, Wise LA, Adami HO, Brinton LA, et al
Obstet Gynecol 2017 06;129(6):1059-1067

Pooled analysis of active cigarette smoking and invasive breast cancer risk in 14 cohort studies.
Gaudet MM, Carter BD, Brinton LA, Falk RT, Gram IT, Luo J, et al
Int J Epidemiol 2017 06;46(3):881-893

Sun Exposure and Psychotic Experiences.
Pilecka I, Sandin S, Reichenberg A, Scragg RKR, David A, Weiderpass E
Front Psychiatry 2017 ;8():107

Prediagnostic Calcium Intake and Lung Cancer Survival: A Pooled Analysis of 12 Cohort Studies.
Yu D, Takata Y, Smith-Warner SA, Blot W, Sawada N, White E, et al
Cancer Epidemiol. Biomarkers Prev. 2017 07;26(7):1060-1070

The Premenopausal Breast Cancer Collaboration: A Pooling Project of Studies Participating in the National Cancer Institute Cohort Consortium.
Nichols HB, Schoemaker MJ, Wright LB, McGowan C, Brook MN, McClain KM, et al
Cancer Epidemiol. Biomarkers Prev. 2017 09;26(9):1360-1369

Associations between sun exposure and other lifestyle variables in Swedish women.
Scragg R, Sandin S, Löf M, Adami HO, Weiderpass E
Cancer Causes Control 2017 Sep;28(9):985-996

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Keywords:
Autism Spectrum Disorder Biostatistics Diabetes Mellitus, Type 1 Epidemiology Genetics Show all
SS
Content reviewer:
Sven Sandin
Gunilla Sonnebring
13-11-2024