Incorporating Functional Genomic Information to Enhance Polygenic Signal and Identify Variants Involved in Gene-by-Environment Interaction for Young Adult Alcohol Problems.

paper Cited Public

Authors: Salvatore, Jessica E; Savage, Jeanne E; Barr, Peter; Wolen, Aaron R; Aliev, Fazil; Vuoksimaa, Eero; Latvala, Antti; Pulkkinen, Lea; Rose, Richard J; Kaprio, Jaakko; Dick, Danielle M
Year: 2018
Journal: Alcoholism, clinical and experimental research
PMID: 29121402
DOI: 10.1111/acer.13551
PMCID: PMC5785466

BACKGROUND: Characterizing aggregate genetic risk for alcohol misuse and identifying variants involved in gene-by-environment (G × E) interaction effects has so far been a major challenge. We hypothesized that functional genomic information could be used to enhance detection of polygenic signal underlying alcohol misuse and to prioritize identification of single nucleotide polymorphisms (SNPs) most likely to exhibit G × E effects. METHODS: We examined these questions in the young adult FinnTwin12 sample (n = 1,170). We used genomewide association estimates from an independent sample to derive 2 types of polygenic scores for alcohol problems in FinnTwin12. Genomewide polygenic scores included all SNPs surpassing a designated p-value threshold. DNase polygenic scores were a subset of the genomewide polygenic scores including only variants in DNase I hypersensitive sites (DHSs), which are open chromatin marks likely to index regions with a regulatory function. We conducted parallel analyses using height as a nonpsychiatric model phenotype to evaluate the consistency of effects. For the G × E analyses, we examined whether SNPs in DHSs were overrepresented among SNPs demonstrating significant G × E effects in an interaction between romantic relationship status and intoxication frequency. RESULTS: Contrary to our expectations, we found that DNase polygenic scores were not more strongly predictive of alcohol problems than conventional polygenic scores. However, variants in DNase polygenic scores had per-SNP effects that were up to 1.4 times larger than variants in conventional polygenic scores. This same pattern of effects was also observed in supplementary analyses with height. In G × E models, SNPs in DHSs were modestly overrepresented among SNPs with significant interaction effects for intoxication frequency. CONCLUSIONS: These findings highlight the potential utility of integrating functional genomic annotation information to increase the signal-to-noise ratio in polygenic scores and identify genetic variants that may be most susceptible to environmental modification.

#	Section	Preview
0	Introduction	Alcohol misuse (i.e., risky drinking and alcohol use disorder) is a top public health problem…
1	Introduction — Characterizing Aggregate Genetic Risk for Alcohol Outcomes	In recent years, polygenic approaches have emerged as one method to characterize aggregate measured…
2	Introduction — Characterizing Aggregate Genetic Risk for Alcohol Outcomes	Polygenic scores can encompass thousands of individual genetic variants spread throughout the genome…
3	Introduction — Characterizing Aggregate Genetic Risk for Alcohol Outcomes	The past decade of genomic research has provided a wealth of information about the genetic variants…
4	Introduction — Characterizing Aggregate Genetic Risk for Alcohol Outcomes	GWAS signals in or near protein-coding regions, and even stronger evidence for overrepresentation of…
5	Introduction — Characterizing Aggregate Genetic Risk for Alcohol Outcomes	In particular, GWAS signals are enriched within regions of open chromatin identified by…
6	Introduction — Characterizing Aggregate Genetic Risk for Alcohol Outcomes	we hypothesized that functional annotation information like DHS location could be used to improve…
7	Introduction — Identifying Genetic Variants Involved in Gene-by-Environment Interaction Effects	Unlike Mendelian disorders such as cystic fibrosis or Huntington’s disease, where a mutation in a…
8	Introduction — Identifying Genetic Variants Involved in Gene-by-Environment Interaction Effects	Among the major criticisms is the focus on “usual suspect” candidate genes in the serotonin or…
9	Introduction — Identifying Genetic Variants Involved in Gene-by-Environment Interaction Effects	whether the DNA is accessible to transcription factors (i.e., the proteins responsible for…
10	Introduction — Identifying Genetic Variants Involved in Gene-by-Environment Interaction Effects	We examined romantic relationship status as the environmental moderator for these analyses in view…
11	Introduction — Identifying Genetic Variants Involved in Gene-by-Environment Interaction Effects	status would be a particularly good “candidate environment” when testing our hypothesis that…
12	Introduction — The Current Study	We examined two research questions related to the incorporation of functional genomic information to…
13	Materials and Method — Sample	Our sample comes from the youngest cohort of the Finnish Twin Cohort Study (FinnTwin12), which was…
14	Materials and Method — Sample	interview at age 14. Follow up of the intensive subsample when twins were, on average, age 22…
15	Materials and Method — Measures — Lifetime alcohol dependence symptoms	The alcohol dependence symptoms (ADsx) measure was the count of the number of lifetime DSM-IV…
16	Materials and Method — Measures — Frequency of intoxication	For the G×E analyses, we expected that the moderating effect of relationship status would be on a…
17	Materials and Method — Measures — Relationship status	Participants were asked, “How long (in years) have you been together with your present partner?”…
18	Materials and Method — Genotyping	Genotyping was conducted using the Human670-QuadCustom Illumina BeadChip (Illumina, Inc., San Diego,…
19	Materials and Method — Genotyping	(versus rare variants), especially in the present sample given the relatively longer LD blocks that…

Name	Type
1000 Genomes Phase I (v3) reference panel local	cohort
1000 Genomes Project	cohort
additive genetic factor local	gene
ADsx	phenotype
ADsx criteria local	phenotype
age	phenotype
aggregate DHS score local	variant
aggregate GW score local	variant
alcohol	phenotype
Alcohol Dependence Symptoms	phenotype
alcohol intoxication	phenotype
Alcohol Problems	phenotype
alcohol problems factor score	phenotype
alcohol-related behaviors	phenotype
alcohol-related outcomes	phenotype
alcohol-related phenotypes	phenotype
Alcohol Use	phenotype
Alcohol Use Disorder	phenotype
ALSPAC	cohort
Avon Longitudinal Study of Parents and Children	cohort
brain tissue samples local	anatomy
complex diseases and traits local	phenotype
complex psychiatric disorders local	phenotype
complex traits	phenotype
cystic fibrosis	phenotype
DHS region variant local	variant
DHSs local	variant
DHS-scores local	cohort
DHS-scores local	drug
DHS SNP local	variant
DHS SNPs local	variant
DHS variants local	variant
discovery GWAS	cohort
DNase I	drug
DNase I-restricted polygenic scores local	drug
ENCODE Project Consortium local	cohort
environment	drug
environmental exposures	drug
environmental inputs local	drug
European ancestry	cohort
Finnish population	cohort
Finnish twins	cohort
Finntwin12	cohort
FinnTwin12 dataset local	cohort
FinnTwin12 study local	cohort
G×E effect local	phenotype
gene-by-environment interaction effects local	phenotype
gene expression	phenotype
genes	gene
genetic variants	cohort
GIANT consortium	cohort
GW-scores local	cohort
GW-scores local	drug
GW SNPs local	variant
HapMap2 CEU local	cohort
Health-related behaviors local	phenotype
height	phenotype
Human670-QuadCustom Illumina BeadChip	drug
Huntington’s disease	phenotype
inferred genotype local	variant
intoxication frequency	phenotype
Intoxication measures local	phenotype
lifetime alcohol use	phenotype
MAOA	gene
mixed European ancestry	cohort
non-DHS SNPs local	variant
non-DHS variants local	variant
phenotype	phenotype
polygenic risk score	cohort
psychiatric assessment at age 22 local	phenotype
regulatory region local	drug
Relationship duration ≥1 year local	phenotype
Relationship involvement local	phenotype
relationship status	phenotype
risky drinking	phenotype
RoadMap tissue lines local	cohort
schizophrenia	phenotype
sex	phenotype
significant G×E effects local	phenotype
SLC6A4	gene
SNP	cohort
The International Schizophrenia Consortium local	cohort
transcription factors	drug
Twin cohort	cohort

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Incorporating Functional Genomic Information to Enhance Polygenic Signal and Identify Variants Involved in Gene-by-Environment Interaction for Young Adult Alcohol Problems.

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