Young Shin Kim, MD, MS, MPH, PhD Child Study Center, Yale University School of Medicine Nathan Kline Institute for Psychiatric Research

Transcription

1 Young Shin Kim, MD, MS, MPH, PhD Child Study Center, Yale University School of Medicine Nathan Kline Institute for Psychiatric Research Exploring the Environmental Causes of Autism and Learning Disabilities December 8 th, 21 The New York Academy of Medicine Hosack Hall New York, New York

2 GEX in ASD Genetics in ASD Environmental Risks of ASD GEX in ASD The Korea Autism Study: GEX in ASD Specific Aims Three Characteristics of the KAS Preliminary Findings Demographic Characteristics of Subjects Distribution of Phenotype and Environmental Risk Factors

3 Twin Studies MX concordance: 6-9% DZ concordance: -1% Sibling Relative Risks: Heritability: 9%

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5 Animal Studies: Different Strains of rat +Borna disease virus > ASD like behavior Human: Advanced maternal age + increased placental trophobalst inclusions > Increased risk for ASD Advanced paternal age > cumulating environmental risks > mutations in male germ cells > Increased risk for ASD

6 Specific Aim 1: To collect biological, phenotype and environmental exposure data in epidemiological samples Epidemiological samples with confirmed ASD (N=5) Epidemiological samples with SRS, ASSQ and BASC phenotype (N=1,) Specific Aim 2: To conduct GEX analyses in ASD Hypothesis 1: Prenatal smoking exposure will increase risks for ASD in children with EN2 risk alleles Hypothesis 2: Advanced parental age at pregnancy will increase risk for ASD in children with risk variants Other exploratory analyses

7 Epidemiological Sample vs. Clinical Sample Minimal selection bias Representative of broader phenotype Population estimate parameters

8 Phenotype Assessment Categorical Phenotype Assessment with ADOS and ADI R Dimensional Phenotype Assessment with ASSQ, SRS and BASC

9 KAS: Total Population Prevalence Study

10 Number Sex Male Female Total SRS No ASD 17 (14.9%) 12 (7.6%) 5 (29.4%) 17 (1%) AD 74 (64.9%) 63 (85.1%) 11 (14.9%) 74 (1%) HPG Other ASD 23 (2.2%) 18 (78.3%) 5 (21.7%) 23 (1%) Total No ASD AD 114 (1%) 93 (81.6%) 21 (18.4%) 114 (1%) 68 (39.5%) 41 (6.3%) 27 (39.7%) 68 (1%) 27 (15.7%) 22 (81.5%) 5 (18.5%) 27 (1%) GPS Other ASD 77 (44.8%) 52 (67.5%) 25 (32.5%) 77 (1%) Total 172 (1%) 115 (66.9%) 57 (33.1%) 172 (1%) M±SD 58±22 93±28 73±23 83±29 46±23 77±22 55±23 55±25

11 HPG GPS IQ No ASD AD Other ASD Total No ASD AD Other ASD Total Very superior 1 (1.4%) 2 (8.7%) 3 (2.6%) 2 (2.9%) 1 (3.7%) 5 (6.5%) 8 (4.7%) Superior 2 (11.8%) 2 (2.7%) 4 (3.5%) 7 (1.3%) 5 (18.5%) 14 (18.2%) 26 (15.1%) Average 12 (7.6%) 22 (29.7%) 13 (56.5%) 47 (41.2%) 51 (75.%) 11 (4.7%) 49 (63.6%) 111 (64.5%) BIF 1 (5.9%) 7 (9.5%) 1 (4.3%) 9 (7.9%) 4 (5.9%) 4 (14.8%) 6 (7.8%) 14 (8.1%) Mild MR 1 (5.9%) 16 (21.6%) 4 (17.4%) 21 (18.4%) 2 (2.9%) 5 (18.5%) 2 (2.6%) 9 (5.2%) Mod MR 2 (27.%) 2 (8.7%) 22 (19.3%) 2 (2.9%) 1 (3.7%) 1 (1.3%) 4 (2.3%) > Severe MR 1 (5.9%) 3 (4.1%) 4 (3.5%) Other MR 3 (4.1%) 1 (4.3%) 4 (3.5%) Mean IQ: HPG= 79±3, GPS=12±2

12 Homogenous Population Ethnically homogenous ancestral group No national aboriginals Minimal immigration and strong social pressures against to non Koreans Rare consanguinity Genetically distinct population

13 Environmental Risk Factor Prevalence 5% 1% 2%

14 Sex Epidemiological Sample with Confirmed ASD Epidemiological Sample without Confirmed ASD Total Sample Male 214 (73%) 997 (52%) 1211 (55%) Female 78 (27%) 917 (48%) 995 (45%) Age (mean ±SD) 1 ±2 years 8 ±2 years 8 ±2 years Birth Order 1 st 78 (31%) 891 (47%) 969 (45%) 2 nd 75 (3%) 782 (41%) 857 (4%) 3 rd 7 (28%) 19 (1%) 26 (12%) 4 th 26 (1%) 33 (2%) 59 (3%)

15 Parental Marital Status Epidemiological Sample with Confirmed ASD Epidemiological Sample without Confirmed ASD Total Sample Married 271 (95%) 139 (74%) 158 (77%) Divorced/Separated 9 (3%) 159 (9%) 168 (8%) Parental Education Widowed 5 (2%) 35 (2%) 4 (2%) Never married (%) 251 (14%) 251 (12%) Mother 12 years 1 (35%) 165 (63%) 1165 (59%) >12 years 188 (65%) 628 (37%) 816 (41%) Father 12 years 59 (2%) 891 (52%) 95 (48%) >12 years 229 (8%) 89 (48%) 138 (52%)

16 Epidemiological Sample without confirmed ASD Epidemiological Sample with confirmed ASD

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18 Parental Age at pregnancy Epidemiological Sample with Confirmed ASD Epidemiological Sample without Confirmed ASD Total Sample Mother > 35years 34 (12.%) 396 (24.%) 43 (22.2%) Father >4 years 19 (6.7%) 337 (2.4%) 356 (18.3%) Prematurity 34 (11.6%) 67 (3.5%) 11 (4.8%) Low Birth Weight 17 (6%) 68 (4%) 85 (4%) Birth Method C Section 111 (39%) 778 (41%) 889 (41%) NSVD 16 (56%) 116 (58%) 1266 (58%) Vacuum/Suction Delivery 16 (6%) 7 (1%) 23 (1%)

19 Epidemiological Sample without confirmed ASD Epidemiological Sample with confirmed ASD Maternal age at pregnancy Paternal age at pregnancy Child s Birth Weight

20 Epidemiological Sample with Confirmed ASD Epidemiological Sample without Confirmed ASD Total Sample Birth Complications 99 (34%) 21 (3%) 12 (12%) Any maternal smoking during pregnancy Any indirect smoking exposure during pregnancy Any maternal drinking during pregnancy 1 (4%) 12 (1%) 22 (1%) 94 (33%) 677 (4%) 771 (39%) 54 (19%) 97 (7%) 151 (9%)

21 First study to examine GEX for the risks of ASD and lack of social reciprocity, using epidemiological sample in a genetically homogenous and distinct population Will provide unique and power complement to the autism research community Exploring roles of GEX in ASD and social reciprocity Large scale gene discovery in ASD and social reciprocity Studying genetic architecture of ASD and social reciprocity

22 Kim Lab Korea Institute for Children s Social Development: Yun Joo Koh Ji Hyun Kim Eun Jeong Lim Bo Young Song Yale: Nancy S Fallon Ryan Blum Dankook University School of Public Health Mina Ha Ho Jang Kwon Soo Jeong Kim State Lab at Yale Matt State Gordon Ober Melanie Raubeson Nicole Wright You Eun Song Nathan Kline Institute Bennett Leventhal

23 Young Shin Kim, MD, MS, MPH, PhD Child Study Center, Yale University School of Medicine Nathan Kline Institute for Psychiatric Research Exploring the Environmental Causes of Autism and Learning Disabilities December 8 th, 21 The New York Academy of Medicine Hosack Hall New York, New York