Table 1

Nicotine dependent vs control comparisons

Gene/Cluster

Class

Chr

Bp

Rep Pos Snps

monte carlo p

Description

CNTN6

CAM

3

1,280,415

11

0.00059

contactin 6

LRRN1

CAM

3

3,769,591

20

0.00007

leucine rich repeat neuronal 1

SEMA3C

CAM

7

80,111,952

9

0.00120

sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3C

CSMD1a

CAM

8

3,184,850

11

0.00083

CUB and Sushi multiple domains 1

CSMD1b

CAM

8

3,653,990

13

0.00095

CUB and Sushi multiple domains 1

PTPRD

CAM

9

8,310,837

13

0.00047

protein tyrosine phosphatase, receptor type, D

LRRN6C$

CAM

9

29,153,017

6

0.00118

leucine rich repeat neuronal 6C

CDH13

CAM

16

81,647,004

11

0.00198

cadherin 13, H-cadherin (heart)

SIPA1L2

ENZ

1

228,796,685

16

0.00040

signal-induced proliferation-associated 1 like 2

PDE4D

ENZ

5

58,461,253

4

0.00329

phosphodiesterase 4D, cAMP-specific (phosphodiesterase E3 dunce homolog, Drosophila)

PDE1C

ENZ

7

31,648,914

8

0.00204

phosphodiesterase 1C, calmodulin-dependent 70 kDa

PRKG1a

ENZ

10

52,485,930

5

0.00299

protein kinase, cGMP-dependent, type I

PRKG1b

ENZ

10

52,986,999

10

0.00214

protein kinase, cGMP-dependent, type I

ELMO1

PROT

7

36,840,767

9

0.00243

engulfment and cell motility 1 (ced-12 homolog, C. elegans)

MICALCL

PROT

11

12,241,526

7

0.00115

MICAL C-terminal like

IMPACT*

PROT

18

20,182,039

9

0.0007

hypothetical protein IMPACT

GRM7

REC

3

6,934,982

5

0.00289

glutamate receptor, metabotropic 7

GPR154*

REC

7

34,383,589

4

0.00123

G protein-coupled receptor 154

HRH4*

REC

18

20,280,986

9

0.0007

histamine receptor H4

NFIB

TF

9

14,190,005

6

0.00274

nuclear factor I/B

KCNQ3*

CHA

8

133,172,472

5

0.00114

potassium voltage-gated channel, KQT-like subfamily, member 3

4

SLC9A9

TRANSP

3

144,947,291

12

0.00333

solute carrier family 9 (sodium/hydrogen exchanger), isoform 9

XKR5*

TRANSP

8

6,650,733

4

0.00063

XK, Kell blood group complex subunit-related family, member 5

ABCC4

TRANSP

13

94,600,083

5

0.0035

ATP-binding cassette, sub-family C (CFTR/MRP), member 4

PTHB1

DIS

7

33,369,755

21

0.00250

parathyroid hormone-responsive B1

ACTN2

STR

1

233,147,888

5

0.00016

actinin, alpha 2

OC90*

STR

8

133,172,472

5

0.00114

otoconin 90

HHLA1*

OTHER

8

133,172,472

12

0.00114

HERV-H LTR-associating 1

DEFB1*

OTHER

8

6,650,733

5

0.00063

defensin, beta 1

FGF14

OTHER

13

101,764,771

12

0.003

fibroblast growth factor 14

A2BP1

OTHER

16

6,603,645

9

0.00171

ataxin 2-binding protein 1

OSBPL1A

OTHER

18

20,182,039

11

0.0007

oxysterol binding protein-like 1A

Nicotine dependent vs control comparisons from the current work add support to previous addict vs control association observations in specific genes. Genes and classes of genes that contain nominally positive (p < 0.005) SNPs in comparisons between nicotine dependent(n = 139) and control (n = 320) individuals in the current study and enhance the significance of previously-obtained whole genome association results for addiction. To be included in this list, the data from the current comparison needs to improve the nominal significance of 100000 Monte Carlo simulation trials by > 10 trials when the current data is added to data from four prior samples. Four prior samples are comprised of genes previously nominated to play roles in addiction based on reproducible nominally positive allele frequency differences between European-American, African-American and Japanese individuals who are dependent on illegal substances or alcohol. Genes in this table this contain: 1) SNPs that display p < 0.005 significance for differences between nicotine dependent and control individuals in the present study 2) clustered SNPs that displayed significant (p < 0.05) differences between both European-American and African-American NIDA polysubstance abusers vs controls in previous studies 3) SNPs that displayed p < 0.05 significance in 100k association genome scans of alcohol dependent vs control individuals (COGA [55]) and 4) SNPs that displayed p < 0.05 significance in 100k association genome scans of methamphetamine dependent vs control individuals (JGIDA [56]).

Genes are identified when positive SNPs lie 1) within the gene's exons or introns or 2) in 3' or 5' flanking sequences that lay within 100 Kb of an annotated exon or extensions of the currently-annotated exons as described [22]. Genes are grouped by the class of the function to which they contribute: "CAM" cell adhesion, "ENZ" enzymes, "PROT" protein processing, "REC" receptors, "TF" transcriptional regulation, "CHA" channels, "TRANSP" transporters, "DIS" disease associated, "STR" structural, "OTHER" other functions. Chromosome number and initial chromosomal position for the cluster (bp, NCBI Mapviewer Build 35.1) are listed. Monte Carlo p values come from 100,000 simulation trials. In each trial, randomly selected sequences lying within randomly selected gene sequences of the same length displayed by the actual genomic segments analyzed here were assessed to determine whether or not they contained at least the number of positive SNPs actually identified for each gene cluster and gene. The frequency of trials in which at least the observed numbers of nominally-positive SNPs were identified in each of the four samples studied here was recorded to provide an empirical p value. Several genes are identified by the same clusters of positive SNPs; these genes are indicated with asterisk symbols. Several genes, identified in several lines of Table 1, contain multiple clusters of reproducibly positive SNPs; the clusters are designated by suffixes a, b etc. We note that the requirements for nominally-significant association signals in each of five samples and increasing significance based on data from the current nicotine dependent vs control comparisons are likely to increase the number of false-negative results; interesting genes that receive support from only four samples are not listed here, for example.

Uhl et al. BMC Genetics 2007 8:10   doi:10.1186/1471-2156-8-10